Cannabinergic Nitrate Esters And Related Analogs

ABSTRACT

The present technology relates to novel cannabinergic nitrate esters and related analogs, process of preparation, pharmaceutical compositions and their methods of use as medicaments, pharmacological tools and/or biomarkers. The novel cannabinergic nitrate ester compounds provide medicaments useful in treating a variety of diseases and medical disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 61/769,410, filed Feb. 26, 2013, which isincorporated herein by reference for any and all purposes.

FIELD

The present technology generally relates to biologically active novelcannabinergic compounds. In particular, the present technology isrelated to novel cannabinergic nitrate esters and related analogs.

BACKGROUND

Human recreational use of the hemp plant Cannabis sativa (“marijuana”)and anecdotal attempts to exploit it for potential therapeutic benefithave been documented throughout millennia. Some of marijuana'spopularity as a recreational substance and medicament reflects itsability to alter sensory perception and relieve anxiety. Other medicinaleffects of marijuana unrelated to its psychoactive properties, such aspain relief, have also been recorded in ancient texts.Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol are the two majorphytocannabinoids that were identified along with approximately 60 otherphytocannabinoids present in Cannabis. Δ ⁹-THC, cannabidiol, and someother phytocannabinoids are bioactive with, for example, intriguinganti-inflammatory, anticonvulsive, and anti-emetic effects of potentialtherapeutic value. However, Δ⁹-THC is regarded as the sole psychotropiccannabinoid in Cannabis. Given Δ⁹-THC's psychotropic effects, manybiological investigations employed brain and brain plasma membranes asstudy-objects. Consensus data describing several key characteristics ofcannabinoid action emerged: Δ⁹-THC, its synthetic analogs and relatedcompounds elicit biological effects in a stereo- and structurallyselective manner; their binding to brain plasma membranes is avid,saturable, stereospecific, concordant with in vitro and in vivobioresponses (e.g., adenylyl cyclase inhibition, analgesia), andnonrandom in select brain regions.

These characteristics strongly implied that cannabinoid pharmacology isreceptor-mediated, spurring the search for discrete mammaliancannabinoid receptors whose activation by Δ⁹-THC would elicitpsychotropic effects. The search led to the discovery and cloning of twoG protein-coupled receptors (GPCRs) for cannabinoids (CB), designatedCB1 and CB2, which in humans share ≈44% sequence homology. The CB1receptor subtype is localized primarily in the central nervous system(CNS), reflecting its prevalence as the most abundant GPCR in brain. CB1receptors are distributed among the cortex, cerebellum, hippocampus, andbasal ganglia, brain regions that control motor, cognitive, emotional,and sensory functions. Hence, central CB1 receptor activation mediatesmost cannabinoid psychotropic and behavioral effects. The CB1 receptoris also present in high density in the brainstem, hypothalamus, andpituitary gland, loci influencing pain perception; hormonal activity;thermoregulation; and cardiovascular, gastrointestinal, and respiratoryphysiology. CB1 receptors at peripheral sites (e.g., adipocytes, liver,uterus) help regulate such basic physiological processes as energybalance and reproduction. Although detectable at exceedingly low levelsin brain, CB2 receptors are expressed mainly by immune and hematopoieticcells, osteoclasts, and osteoblasts and mediate immune responses,inflammation, inflammatory and neuropathic pain, and bone remodeling.Largely because of this psychoactivity as well as its prevalence andearly availability in synthetic form as a research tool, Δ⁹-THC attainedthe status of prototypic cannabinoid and became the focus of manypharmacological and mechanistic studies.

Much of this research in vivo was aimed at elucidating the effects ofΔ⁹-THC in experimental animals as well as human subjects with the aid ofnewly-synthesized Δ⁹-THC analogs and related compounds such as nabilone,Δ⁸-tetrahydrocannabinol, 11-OH-Δ⁹-tetrahydrocannabinol, cannabidiol(ex., GWP42003), cannabinol, Δ⁹-tetrahydrocannabivarin (ex., GWP42004),CP-47,497, dexanabinol, Ajulemic acid, HU-210,8-β-OH-tetrahydrocannabinol, 8-α-OH-tetrahydrocannabinol, SAB-378,nabitan, menabitan, A-40174, Org 28611, nonabine, BAY38-7271, GRC10693,S-777469, AZD¹940, GW-842,166X, GW-405,833, levonantradol,dimethylheptylpyran and the AM1703 analog PRS-211,375 (Cannabinor). Someof these compounds were radiolabeled and used as molecular probes aswell. Virtually all cannabinoid-related medications granted regulatoryapprovals thus far are directly related to Cannabis, most of which actas agonists at the CB1 and CB2 receptors.

It has been suggested that tetrahydrocannabivarin acts as a CB1 neutralantagonist while Δ⁹-THC is known to act as a CB1 partial agonist. Δ⁹-THC(dronabinol, Marinol®) and its synthetic analog, the CB1/CB2 agonist,nabilone (Cesame®) are licensed as anti-nausea and anti-emeticmedications for chemotherapy patients. Nabilone is also approved as anappetite stimulant to treat acquired immune deficiency syndrome-relatedcachexia. Sativex®, a standardized Cannabis extract containing anapproximately equal mixture of the two phytocannabinoids (Δ⁹-THC andcannabidiol) formulated as a sublingual spray, was first licensed foralleviation of neuropathic pain in multiple sclerosis patients andsubsequently approved for cancer pain relief. The low reported frequencyof abuse and neurocongnitive side-effects of Cannabis extracts/Δ⁹-THCderivatives has invited their continued clinical evaluation. Aside fromnabilone, other synthetic cannabinoid-receptor activators such asCP55,940 have been studied clinically for alleviation of emesis;motor-related symptoms in patients with multiple sclerosis, Tourette'ssyndrome, or Parkinson's disease; intraocular pressure in glaucomapatients; neuropathic pain; or post-trauma brain damage.

SUMMARY

In one aspect, a compound of formula (I), or a pharmaceuticallyacceptable salt thereof is provided:

wherein:

-   -   C has zero, one, two or three double bonds;    -   X is C, CH, N, NH, C(CH₂)₂, S, O, SO, SO₂, or CF₂;    -   R is H, OH, ═O, halogen, COOH, nitro, ONO₂, or optionally        substituted alkyl, haloalkyl, alkenyl, alkynyl, acyl, aryl,        heterocyclyl, heteroaryl, alkoxy, aryloxy, heteroalkoxy,        heteroaryloxy, alkenyl, amino, thio, cyano, thiocynato,        isothiocynato, carboxyl, formyl, carbamyl, amino, acylamino,        amido, imido, aminoalkyl, aminoaryl, heteroarylamino,        heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl,        thioaryl, heteroarylthio, heterocyclylthio, phosphonate,        phosphate, or acetate;    -   W is C(CH₃)₂, CH(CH₃), C═O, C(O)-alkyl, C<F₂, C═S, C═CH₂,        C(CH₂)₂, spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)];    -   R⁴ is an optionally substituted alkyl, alkenyl, or alkynyl        group;    -   Z is O, S, SO, SO₂, NH, N—CN or N-alkyl;    -   R is H, OH, SH, NH₂, CF₃, COOH, halogen, ONO₂, alkyl-ONO₂, or        optionally substituted alkyl, haloalkyl, amine, amide, imide,        alkoxy, alkoxy thio, phosphate, phosphonatc, carboxyl, formyl,        carbamyl, amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl group;    -   R³ is absent, or is O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl,        alkenyl, alkynyl, cycloalkyl, a carbocyclic, a spirocyclic,        heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine, amide,        or imide;    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronatc ester, BF₃K, or a biotin        group tethered via an amide bond.

In Formula I, in some embodiments, C has at least one double bond at theC8-C9 position, the C9-C10 position, or the C6a-C10a position. In someembodiments, V is ONO₂. In other embodiments, R¹ is a group comprisingONO₂ and V is H. In other embodiments, R¹ is ONO₂, alkyl-ONO₂,O-alkyl-ONO₂, O—SO₂-alkyl-ONO₂, —C(O)O-alkyl-ONO₂,alkyl-C(O)O-alkyl-ONO₂, or alkyl-O-alkyl-ONO₂. In some embodiments, Chas one, two or three double bonds, and at least one double bond is atthe C8-C9 position, the C9-C10 position, or the C6a-C10a position; W isC(CH₃)₂, CH(CH₃), C═O, or CF₂; Z is O or N; and V is H when R¹ is agroup including ONO₂, or V is ONO₂. In any of the above embodiments,Y—R³—V may be ONO₂, alkyl-ONO₂, O-alkyl-ONO₂, O—SO₂-alkyl-ONO₂,—C(O)O-alkyl-ONO₂, alkyl-C(O)O-alkyl-ONO₂, or alkyl-O-alkyl-ONO₂.

In any of the above embodiments of Formula I, C may be:

In any of the above embodiments of Formula I, B may be:

In any of the above embodiments of Formula I, C may be:

B may be:

and V is ONO₂.

In another aspect, provided is a compound of Formula (II), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C is carbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a        terpene;    -   G is a bond, C═O, NH, CH₂, CONH, NHCO, C(O)O, OC(O), OCH₂, S,        SO, SO₂, or O;    -   A is an aromatic ring, heteroaromatic ring, heterocyclic ring,        or quinone;    -   R^(2a) and R^(2b) are each independently H, OH, SH, NH₂, CF₃,        COOH, halogen, ONO₂, alkyl-ONO₂, or optionally substituted        alkyl, haloalkyl, amine, amide, imide, alkoxy, alkoxy thio,        phosphate, phosphonate, carboxyl, formyl, carbamyl, amino,        acylamino, amido, imido, aminoalkyl, aminoaryl, heteroarylamino,        heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl,        thioaryl, heteroarylthio, heterocyclylthio, phosphonate,        phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl group;    -   R³ is absent, or is O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl,        alkenyl, alkynyl, cycloalkyl, a carbocyclic, a spirocyclic,        heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine, amide,        or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In any of the above embodiments of Formula II, C may be:

In any of the above embodiments of Formula II, A may be:

In another aspect, provided is a compound of Formula (III), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C is carbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a        terpene;    -   R^(2a) and R^(2b) are each independently H, OH, SH, NH₂, CF₃,        COOH, halogen, ONO₂, alkyl-ONO₂, or optionally substituted        alkyl, haloalkyl, amine, amide, imide, alkoxy, alkoxy thio,        phosphate, phosphonate, carboxyl, formyl, carbamyl, amino,        acylamino, amido, imido, aminoalkyl, aminoaryl, heteroarylamino,        heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl,        thioaryl, heteroarylthio, heterocyclylthio, phosphonate,        phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl;    -   R³ is absent, O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl,        alkynyl, cycloalkyl, a carbocyclic, a spirocyclic, heterocyclyl,        aryl, heteroaryl, carboxyl, acetate, amine, amide, or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronatc ester, BF₃K, or a biotin        group tethered via an amide bond.

In any of the above embodiments of Formula III, C may be:

In another aspect, provided is a compound of Formula (TV), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C is carbocyclic, bicyclic, acyl, heterocyclyl, heteroaryl, or a        terpene;    -   R^(2a) and R^(2b) are each independently H, OH, SH, NH₂, CF₃,        COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂, or optionally        substituted alkyl, haloalkyl, amine, amide, imide, alkoxy,        alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or, alkynyl;    -   R³ is absent, or is O, S, SO₂, SO₂NH, NHSO₂, or OSO₂, alkyl,        alkenyl, alkynyl, cycloalkyl, a carbocyclic, a spirocyclic,        heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine, amide,        or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, C1, Br, T, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In any of the above embodiments of Formula IV, C may be:

In another aspect, provided is a compound of Formula (V), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   X is C, CH, N, NH, (CH₂)₂N, S, O, SO, SO₂, or CF₂;    -   R¹ is H, OH, ═O, halogen, COOH, nitro, ONO₂, alkyl, haloalkyl,        alkenyl, alkynyl, acyl, aryl, heterocyclyl, heteroaryl, alkoxy,        aryloxy, heteroalkoxy, heteroaryloxy, alkenyl, amino, thio,        cyano, thiocynato, isothiocynato, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   R^(2a) and R^(2b) are each independently H, OH, SH, NH₂, CF₃,        COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂, or optionally        substituted alkyl, haloalkyl, amine, amide, imide, alkoxy,        alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S, SO,        SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl;    -   R³ is absent, or is O, S, SO₂, SO₂NH, NHSO₂, or OSO₂, alkyl,        alkenyl, alkynyl, cycloalkyl, a carbocyclic, a spirocyclic,        heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine, amide,        or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In another aspect, provided is a compound of Formula (VI), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C is carbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a        terpene;    -   M is CH₂ or alkyl-T¹;    -   L is CH₃ or alkyl-r; and    -   X is C, CH, N, NH, (CH₂)₂N, S, O, SO, SO₂, or CF₂;    -   R¹ is H, OH, ═O, halogen, COOH, nitro, ONO₂, alkyl, haloalkyl,        alkenyl, alkynyl, acyl, aryl, heterocyclyl, heteroaryl, alkoxy,        aryloxy, heteroalkoxy, heteroaryloxy, alkenyl, amino, thio,        cyano, thiocynato, isothiocynato, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   R^(2a) and R^(2b) are each independently H, OH, SH, NH₂, CF₃,        COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂, or optionally        substituted alkyl, haloalkyl, amine, amide, imide, alkoxy,        alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sulfonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl;    -   R³ is absent, O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl,        alkynyl, cycloalkyl, a carbocyclic, a spirocyclic, heterocyclyl,        aryl, heteroaryl, carboxyl, acetate, amine, amide, or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO, V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In any of the above embodiments of Formula VI, C may be:

In another aspect, provided is a compound of Formula (VII), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C is carbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a        terpene;    -   P is H, alkyl, alkyl-OH or alkyl-ONO₂;    -   X is C, CH, N, NH, (CH₂)₂N, S, O, SO, SO₂, or CF₂;    -   R¹ is H, OH, ═O, halogen, COOH, nitro, ONO₂, alkyl, haloalkyl,        alkenyl, alkynyl, acyl, aryl, heterocyclyl, heteroaryl, alkoxy,        aryloxy, heteroalkoxy, heteroaryloxy, alkenyl, amino, thio,        cyano, thiocynato, isothiocynato, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   R^(2a) and R^(2b) are each independently H, OH, SH, NH₂, CF₃,        COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂, or optionally        substituted alkyl, haloalkyl, amine, amide, imide, alkoxy,        alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl;    -   R³ is absent, O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl,        alkynyl, cycloalkyl, a carbocyclic, a spirocyclic, heterocyclyl,        aryl, heteroaryl, carboxyl, acetate, amine, amide, or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In any of the above embodiments of Formula VII, C may be:

In another aspect, provided is a compound of Formula (VIII), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C is carbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a        terpene;    -   G is a bond, C═O, NH, CH₂, CONH, NHCO, C(O)O, OC(O), OCH₂, S,        SO, SO₂, or O;    -   W is C(CH₃)₂, CH(CH₃), C═O, C(O)-alkyl, CF₂, C═S, C═CH₂,        C(CH₂)₂, spirocyclic ring, S, SO, SO₂, or C[CH₃(R)];    -   R⁴ is alkyl, alkenyl, or alkynyl group;    -   Z is O, S, SO, SO₂, NH, or N-alkyl;    -   R² is H, OH, SH, NH₂, CF₃, COOH, alkoxy, halogen, ONO₂,        alkyl-ONO₂, alkyl, haloalkyl, amine, amide, imide, alkoxy,        alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, alkynyl;    -   R³ is absent, O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl,        alkynyl, cycloalkyl, a carbocyclic, a spirocyclic, heterocyclyl,        aryl, heteroaryl, carboxyl, acetate, amine, amide, or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In another aspect, provided is a compound of Formula (IX), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C is carbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a        terpene;    -   n=0, 1    -   W is C(CH₃)₂, CH(CH₃), C═O, C(O)-alkyl, CF₂, C═S, C═CH₂,        C(CH₂)₂, spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)];    -   R⁴ is alkyl, alkenyl, or alkynyl;    -   Z is O, S, SO, SO₂, NH, or N-alkyl;    -   R² is H, OH, SH, NH₂, CF₃, COOH, alkoxy, halogen, ONO₂,        alkyl-ONO₂, alkyl, haloalkyl, amine, amide, imide, alkoxy,        alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,        phosphonate, phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl;    -   R³ is absent, O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl,        alkynyl, cycloalkyl, a carbocyclic, a spirocyclic, heterocyclyl,        aryl, heteroaryl, carboxyl, acetate, amine, amide, or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), a spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In any of the above embodiments of Formula VII, C may be:

According to various embodiments, any of the above compounds may includewhere:

C is aromatic and A is aromatic, and G is C═O;

C is aromatic and A is heteroaromatic, and G is C═O;

C is aromatic and A is heteroaromatic, and G is CONH;

C is heterocyclic and A is heteroaromatic, and G is C═O;

C is heterocyclic and A is heteroaromatic, and G is C═O;

C is alkyl and A is heteroaromatic, and G is C═O;

C is carbocyclic and A is heteroaromatic, and G is C═O;

C is alkyl and A is heteroaromatic, and G is CONH;

C is heteroaromatic and A is heteroaromatic, and G is N(alkyl)SO₂;

C is aromatic and A is heteroaromatic, and G is NH;

C is bicyclic ring and A is aromatic, and G is O;

C is bicyclic ring and A is aromatic, and G is a direct bond;

C is a terpene;

C is carbocyclic and W is optionally present;

C is heteroaromatic and A is heteroaromatic, and G is OCH₂;

C is heterocyclic and A is aromatic, and G is CH₂;

C is aromatic and A is heterocyclic, and G is CH₂;

C is carbocyclic and A is heteroaromatic, and G is a COO or OCO;

C is heterocyclic and A is aromatic, and G is a direct bond;

C is heterocyclic and A is heteroaromatic, and G is a direct bond;

C is a terpene and A is aromatic, and G is a direct bond;

C is a terpene and A is quinone, and G is a direct bond;

C is a terpene and A is aromatic, and G is a direct bond;

C is heterocyclic and A is aromatic, and G is a direct bond;

C is aromatic and A is aromatic, and G is a direct bond;

C is aromatic and A is heterocyclic, and G is a direct bond;

C is alkyl and A is heteroaromatic, and G is a direct bond;

C is a terpene and A is aromatic, and G is a direct bond;

C is bicyclic and W is C═O; or

C is carbocyclic, B is carbocyclic and A is aromatic.

In another aspect, a compound is provided that is:

In another aspect, a composition is provided, the composition includingany of the above compounds and at least one pharmaceutically acceptableexcipient.

In another aspect, a method of agonizing activity of a cannabinoid 1(CB1), cannabinoid 2 (CB2) or GPR55 receptor is provided, the methodincluding contacting the cannabinoid 1 (CB1), cannabinoid 2 (CB2) orGPR55 receptor with a compound including a nitrate ester.

In another aspect, a method of agonizing activity of a cannabinoid 1(CB1), cannabinoid 2 (CB2) or GPR55 receptor is provided, the methodincluding contacting the cannabinoid 1 (CB1), cannabinoid 2 (CB2) orGPR55 receptor with any of the compounds described herein.

In another aspect, a method of antagonizing activity of a cannabinoid 1(CB1), cannabinoid 2 (CB2) or GPR55 receptor is provided, the methodincluding contacting the cannabinoid 1 (CB1), cannabinoid 2 (CB2) orGPR55 receptor with a compound including a nitrate ester.

In another aspect, a method of antagonizing activity of a cannabinoid 1(CB1), cannabinoid 2 (CB2) or GPR55 receptor is provided, the methodincluding contacting the cannabinoid 1 (CB1), cannabinoid 2 (CB2) orGPR55 receptor with any of the compounds described herein.

In another aspect, a method of inhibiting activity of a cannabinoid 1(CB1), cannabinoid 2 (CB2) or GPR55 receptor is provided, the methodincluding contacting the cannabinoid 1 (CB1), cannabinoid 2 (CB2) orGPR55 receptor with a compound including a nitrate ester.

In another aspect, a method of inhibiting activity of a cannabinoid 1(CB1), cannabinoid 2 (CB2) or GPR55 receptor is provided, the methodincluding contacting the cannabinoid 1 (CB1), cannabinoid 2 (CB2) orGPR55 receptor with any of the compounds described herein.

In any of the above methods, the compound that includes the nitrateester may be compound of formula (T)

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   C has zero, one, two or three double bonds;    -   X is C, CH, N, NH, (CH₂)₂N, S, O, SO, SO₂, or CF₂;    -   R is H, OH, ═O, halogen, COOH, nitro, ONO₂, alkyl, haloalkyl,        alkenyl, alkynyl, acyl, aryl, heterocyclyl, heteroaryl, alkoxy,        aryloxy, heteroalkoxy, heteroaryloxy, alkenyl, amino, thio,        cyano, thiocynato, isothiocynato, carboxyl, formyl, carbamyl,        amino, acylamino, amido, imido, aminoalkyl, aminoaryl,        heteroarylamino, heterocyclylamino, sulfonate, sufonamide,        sulfonyl, thioalkyl, thioaryl, heteroaiylthio, heterocyclylthio,        phosphonate, phosphate, acetate group;    -   W is C(CH₃)₂, CH(CH₃), C═O, C(O)-alkyl, CF₂, C═S, C═CH₂,        C(CH₂)₂, spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)];    -   R⁴ is alkyl, alkenyl, or alkynyl;    -   Z is O, S, SO, SO₂, NH, or N-alkyl;    -   R² is H, OH, SH, NH₂, CF₃, COOH, halogen, ONO₂, alkyl-ONO₂,        alkyl, haloalkyl, amine, amide, imide, alkoxy, alkoxy thio,        phosphate, phosphonate, carboxyl, formyl, carbamyl, amino,        acylamino, amido, imido, aminoalkyl, aminoaryl, heteroarylamino,        heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl,        thioaryl, heteroaiylthio, heterocyclylthio, phosphonate,        phosphate, or acetate;    -   Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH,        alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S,        SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl;    -   R³ is absent, O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl,        alkynyl, cycloalkyl, a carbocyclic, a spirocyclic, heterocyclyl,        aryl, heteroaryl, carboxyl, acetate, amine, amide, or imide; and    -   V is V¹ or ONO₂, wherein when any of rings A, B or C is        substituted with a group comprising ONO₂ V is V¹, otherwise V is        ONO₂; and    -   V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,        amino, alkylamino, dialkylamino, trialkylamino, aryl,        cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl,        —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino),        C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl,        —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,        OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl,        —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,        —SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl,        Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H,        C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl), SO₂(trialkylamino),        SO₂(dialkylamino), spirocyclic ring, heterocyclyl, heteroaryl,        alkylthio, alkylamino, dialkylamino, alkylsulfinyl,        alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin        group tethered via an amide bond.

In another aspect, a method is provided for treating a conditionmodulated by CB1, CB2 receptors and/or the GPR55 receptor activity, themethod including administering to a subject in need thereof atherapeutically effective amount of any of the compounds describedherein.

In another aspect, a method is provided for treating a conditionmodulated by CB1, CB2 receptors and/or the GPR55 receptor activity, themethod including administering to a subject in need thereof atherapeutically effective amount of a compound including a nitrate estermoiety.

In another aspect, a use of a cannabinoid receptor agonist or acannabinoid receptor antagonist for the manufacture of a medicament forthe treatment of a condition modulated by CB1, CB2 receptors and/or theGPR55 receptor activity, wherein the cannabinoid receptor agonist orantagonist is compound including a nitrate ester moiety. In suchembodiments, the compound may be an agonist or antagonist of a CB1, CB2or GPR55 receptor, or combination of any two or more such receptors. Insome such embodiments, the compound is a full agonist, a partialagonist, a neutral agonist, an inverse agonist, a full antagonist, apartial antagonist, a neutral antagonist, or an inverse antagonist. Insome embodiments, the cannabinoid receptor inverse agonist orcannabinoid receptor neutral antagonist is a CB1 inverse agonist or aCB1 neutral antagonist or a CB2 inverse agonist or a CB2 neutralantagonist. In some embodiments, the cannabinoid receptor agonist orcannabinoid receptor antagonist is any of the compounds describedherein.

In another aspect, the compounds described herein are capable of forminga covalent bond with an amino acid residue within the CB1, CB2 or GPR55cannabinoid receptor. In some embodiments, the compound forms a covalentbond with an amino acid residue within the allosteric site ororthosteric site of the CB1, CB2 or GPR55 cannabinoid receptor. In someembodiments the compound acts as a nitric oxide donor. In someembodiments, the compound acts as a nitric oxide donor and forms acovalent bond with an amino acid residue within the cannabinoidreceptor. In some embodiments, the compound acts as an allostericmodulator of the cannabinoid receptor. In some embodiments, the compoundacts as an allosteric modulator and an orthosteric modulator of thecannabinoid receptor.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodimentsand features described above, further aspects, embodiments and featureswill become apparent by reference to the following drawings and thedetailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates chemical structures of Δ⁸-THC, Δ⁹-THC, cannabidiol,abnormal cannabidiol, compound 1, compound 78, compound 84 and compound117.

FIG. 2 illustrates covalent binding of compound 1 to hCB2.

FIG. 3 illustrates covalent binding of compound 84 to rCB1.

FIG. 4 illustrates rCB1 competition binding for compound 1.

FIG. 5 illustrates mCB2 competition binding for compound 1.

FIG. 6 illustrates hCB2 competition binding for compound 1.

FIG. 7 illustrates rCB1 cAMP data for compound 1.

FIG. 8 illustrates hCB2 cAMP data for compound 1.

FIG. 9 illustrates rCB1 cAMP data for compound 78.

FIG. 10 illustrates hCB2 cAMP data for compound 78.

FIG. 11 is a comparison of antinociception data (tail immersion test)between morphine, Δ⁹-THC and compound 1 in mice.

FIG. 12 illustrates antinociception data (tail immersion test) forcompound 1 at 0.1 mg/kg and 1 mg/kg over 24 hours in mice.

FIG. 13 illustrates antinociception data (tail immersion test) forcompound 84 cumulatively dosed up to 1 mg/kg in mice.

FIG. 14 illustrates antinociception data (tail immersion test) forcompound 117 cumulatively dosed up to 10 mg/kg in mice.

FIG. 15 illustrates the biochemical assay for compound 78 wherein theβ-arresting assessment of GPR55 activation is shown.

DETAILED DESCRIPTION

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a solvent” includes aplurality of such solvents.

As used herein, the term “comprising” or “comprises” is intended to meanthat the compositions and methods include the recited elements, but notexcluding others. “Consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination for the stated purpose. Thus,a composition or process consisting essentially of the elements asdefined herein would not exclude other materials or steps that do notmaterially affect the basic and novel characteristic(s) of the claimedtechnology. “Consisting of” shall mean excluding more than traceelements of other ingredients and substantial method steps. Embodimentsdefined by each of these transition terms are within the scope of thistechnology.

The term “compound(s) of the technology” as used herein means any ofcompounds of formulae (I)(IX), and may include stereoisomers, salts,tautomeric forms, hydrates and/or solvates thereof. The compounds of thepresent technology are prepared in different forms, such aspharmaceutically acceptable salts, hydrates, or solvates and thetechnology includes compositions and methods encompassing all variantforms of the compounds.

As used herein, C_(m)-C_(n), such as C₁-C₁₂, C₁-C₈, or C₁-C₆ when usedbefore a group refers to that group containing m to n carbon atoms.

Unless otherwise specifically defined, “acyl” refers to the generalformula —C(O)alkyl.

Unless otherwise specifically defined, “acyloxy” refers to the generalformula O-acyl.

Unless otherwise specifically defined, “alcohol” refers to the generalformula alkyl-OH or carbocyclic-OH, cyclic alkyl-OH, and includesprimary, secondary and tertiary variations. The alcohol can be protectedwith a protecting group selected from Peter G. M. Wuts, Theodora W.Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition,2006, Wiley; herein incorporated by reference in its entirety. Examplesof protecting groups include methyl, benzyl and acetyl.

Unless otherwise specifically defined, “alkyl” or “lower alkyl” refersto a linear, branched or cyclic or cyclo-alkyl group having from 1 to 30carbon atoms, 1 to 12 carbon atoms, and 1 to 7 carbon atoms including,for example, methyl, ethyl, propyl, butyl, hexyl, octyl, isopropyl,isobutyl, tert-butyl, cyclopropyl, cyclohexyl, and cyclooctyl. The alkylgroup can be saturated or unsaturated. The alkyl group or the loweralkyl group can be unsubstituted, singly substituted or, if possible,multiply substituted, with substituent groups in any possible position.Unless otherwise specifically limited, a cyclic or cyclo-alkyl groupincludes monocyclic, bicyclic, tricyclic, tetracyclic and polycyclicrings, for example adamantyl, oxa-adamantyl, norbornyl, terpenes andrelated derivatives.

Unless otherwise specifically defined, “alkenyl” refers to a, straightor branched hydrocarbon chain containing 2 to 12 carbons and containingat least one carbon-carbon double bond. Representative alkenyl groupsinclude vinyl, allyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl,2-methylhex-2-enyl, 3-butenyl, 2-methylpent-2-enyl,3-methylocta-2,6-dienyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,2-methyl-1-heptenyl, and 3-decenyl. The “alkenyl” group can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position.

Unless otherwise specifically defined, “alkenylene” refers to a divalentgroup derived from a straight or branched hydrocarbon chain containing 2to 4 carbon atoms and containing at least one carbon-carbon double bond.Representative alkenylene groups include, CH═CH— and —CH₂CH═CH—. The“alkenylene” group can be unsubstituted, singly substituted or, ifpossible, multiply substituted, with substituent groups in any possibleposition.

Unless otherwise specifically defined, “alkynyl” refers to a straight orbranched chain hydrocarbon group containing 2 to 10 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativealkynyl groups include acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl. The “alkynyl” group can be unsubstituted,singly substituted or, if possible, multiply substituted, withsubstituent groups in any possible position

Unless otherwise specifically defined, “alkoxy” refers to the generalformula O-alkyl. The “alkoxy” group can be unsubstituted, singlysubstituted or, if possible, multiply substituted, with substituentgroups in any possible position

Unless otherwise specifically defined, “alkylmercapto” refers to thegeneral formula S-alkyl.

Unless otherwise specifically defined, “alkylamino” refers to thegeneral formula —(NH)-alkyl.

Unless otherwise specifically defined, “di-alkylamino” refers to thegeneral formula N-(alkyl)₂. Unless otherwise specifically limiteddi-alkylamino includes cyclic amine compounds such as piperidine andmorpholine.

Unless otherwise specifically defined, an “aromatic” ring is anunsaturated ring structure having about 6 to 12, about 6 to 8 ringmembers, for example benzene and naphthalene. The aromatic ringstructure can be unsubstituted, singly substituted or, if possible,multiply substituted, with substituent groups in any possible position.

Unless otherwise specifically defined, “aryl” refers to an aromatic ringsystem, for example phenyl, biphenyl or naphthyl. The aryl group can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position. In certainembodiments, the aryl group will be fused to a carbocyclic ring having 5to 8 ring atoms, for example as in 2,3-dihydro-1H-indene,2,3-dihydro-1H-inden-2-yl)methanol and2,2-dimethyl-2,3-dihydro-1H-indene. In certain embodiments, the arylgroup will be fused to a heterocyclic ring having from 5 to 8 ringatoms, for example as in chromane and 2,3-dihydrobenzofuran.

Unless otherwise specifically defined, “aroyl” refers to the generalformula —C(═O)aryl. The “aroyl” group can be unsubstituted, singlysubstituted or, if possible, multiply substituted, with substituentgroups in any possible position

Unless otherwise specifically defined, a “bicyclic” ring structurecomprises 2 fused or bridged rings. The bicyclic ring structure can besaturated or unsaturated. The bicyclic ring structure can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position. The individual ringsmay or may not be of the same type. Examples of bicyclic ring structuresinclude, 2,3-dihydro-1H-indene, bicyclo[3.1.0]hexane,2,3-dihydro-1H-inden-2-yl)methanol, bicyclooctane7,7-dimethylbicyclo[2.2.1]hept-2-ene,7,7-dimethylbicyclo[2.2.1]hept-2-en-1-yl)methanol,7,7-dimethylbicyclo[2.2.1]heptane, 2,6-dioxabicyclo[3.3.0]octane,6,6-dimethylbicyclo[3.1.1]heptan-2-one, tetralin, decalin and relatedterpenes such as caranc, trans-thujane, pinnae, camphene, isocamphane,fenchane, careen, chaminic acid, sabinene, thujene, thujol, thujanone,α-pinene, β-pinene, car-4-ene-3-ol, verbenol, verbenone, myrtenol,myrtenal, pinocarveol, pinocarvone, camphor, isoborneol, borneol,norbornane, fenchone, β-fenchol, α-fenchol, camphene and fenchene. Theterpenes will encompass all related isomers and derivatives.

Unless otherwise specifically defined, a “carbocyclic” group and all itsisomers is a non-aromatic ring structure, chiral or achiral, saturatedor unsaturated, substituted or unsubstituted, with about 0 to 5heteroatoms, and having about 3 to about 20 ring members, for example,1- or 2-cyanocyclopropyl, 2,2,3,3-tetramethylcyclopropyl,cyclohexadiene, cyclohexanol, cycloheptane, cyclohexane,tetrahydropyran, cyclohexanone, cyclohexene, cyclohexadiene, lactone,lactam, sultone, sultam, quinone, and terpenes. The carbocyclic groupand all of its isomers can be unsubstituted, singly substituted or, ifpossible, multiply substituted, with substituent groups in any possibleposition. Carobocyclic groups related to terpenes include(+)-cis/trans-p-mentha-2,8-dien-1-ol((1S,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol and(1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol),p-mentha-1,8-diene-3-ol (isopiperitenol), nopinone and relatedderivatives, menthane, limonene, phellandrene, terpinolene, terpinene,menthol, isomenthol, neomenthol, neoisomenthol, pulegol, isopulegol,piperitol, terpineol, menth-1-en-8-thiol, carveol, perillaaldehyde,perillyl alcohol, menthone, isomenthone, pulegone, isopulegone,phellandral, piperitone, dihydrocarvone, carvenone, carvone, cymene,carvacrol, thymol, cymen-8-ol and cuminaldehyde. The terpenes willencompass all related isomers. In certain embodiments, the carbocylicgroup can be fused to another carbocyclic group, for example as inoctahydro-1H-indene. Carobocyclic groups comprising of lactones includeα-acetolactone, β-propiolactone, γ-butyrolactone, δ-valerolactone andε-caprolactone. In some instances, a carbocyclic group can also be acyclic or cycloalkyl group, a heteroalkyl or a heterocyclic group, or analkyl group.

Unless otherwise specifically defined, an “alkaloid” is a naturalproduct as defined in the publication Alkaloids—Secrets of Life,Alkaloid Chemistry, Biological Significance, Applications and EcologicalRole by Tadeusz Aniszewski, 2007, Elsevier B.V., herein incorporated byreference in its entirety. Examples include morphine, codeine, andthebaine. The “alkaloid” can be unsubstituted, singly substituted or, ifpossible, multiply substituted, with substituent groups in any possibleposition.

Unless otherwise specifically defined, a lactone is a cyclic esterhaving 4 to 8 ring members. The lactone can be unsubstituted, singlysubstituted or, if possible, multiply substituted, with substituentgroups in any possible position.

Unless otherwise specifically defined, a lactam is a cyclic amide having4 to 8 ring members. The lactam can be unsubstituted, singly substitutedor, if possible, multiply substituted, with substituent groups in anypossible position.

Unless otherwise specifically defined, a sultam is a cyclic sulfonamidehaving 4 to 8 ring members in which the S—N bond is part of the ring.The sultam can be unsubstituted, singly substituted or, if possible,multiply substituted, with substituent groups in any possible position.

Unless otherwise specifically defined, a “terpene” is a natural productas defined within and in the publication Terpenes—Flavors, Fragrances,Pharmaca, Pheromones (Eberhard Breitmaier, 2006, Wiley-VCH, incorporatedherein by reference in its entirety). Examples of terpenes includecamphor, pinene and menthol. The “terpene” can be unsubstituted, singlysubstituted or, if possible, multiply substituted, with substituentgroups in any possible position. In some embodiments, a terpene can alsobe an carbocyclic group or an alkyl group. Unless otherwise specificallydefined, a “terpene derivative” is a natural product or a syntheticcompound that is obtained by a chemical modification of another parentterpene. For example, (+)-nopinone can be derived from β-pinene and.Similarly cis- and trans-isopiperitenol can be derived from the(+)-limonene.

Unless otherwise specifically defined, “halogen” refers to an atomselected from fluorine, chlorine, bromine and iodine.

Unless otherwise specifically defined, a “heteroaromatic” ring is anunsaturated ring structure having about 5 to about 8 ring membersindependently selected from carbon atoms and one or more heteroatoms,including oxygen, nitrogen, phosphorous and/or sulfur, for example,thiophene, oxazole, isoxazole, imidazole, pyrazole, benzimidazole,triazolopyridine, benzotriazole, pyridine, pyridine 1-oxide, pyrimidine,indole, indazole, furan, quinoline, 1,2,4-triazole, 1,2,3-triazole,imidazole, tetrazole, 1H-pyrrolo[2,3-c]pyridine,1H-pyrrolo[2,3-b]pyridine, 1-(cyclohexylmethyl)-1H-benzo[d]imidazole,1-((1-methylpiperidin-2-yl)methyl)-1H-indole,2,3,4,9-tetrahydro-1H-carbazole, 1,2,3,4-tetrahydropyrrolo[3,4-b]indole,4-(alkylsulfonyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole,quinazolin-4(3H)-one, 4-((1H-indol-1-yl)methyl)tetrahydro-2H-thiopyran1,1-dioxide, isoindolin-1-one, nucleosides and their derivatives. Theheteroaromatic ring can be unsubstituted, singly substituted or, ifpossible, multiply substituted, with substituent groups in any possibleposition. In certain embodiments, the heteroaryl group will be fused toa carbocyclic group having 5 to 8 ring atoms, for example as in4,5,6,7-tetrahydrobenzo[b]thiophene,4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole and4,5,6,7-tetrahydro-1H-indole. In certain embodiments, the heteroarylgroup will be fused to a heterocyclic ring having from 5 to 8 ringatoms, for example as in 5,6,7,8-tetrahydroquinoline.

Unless otherwise specifically defined, a “heterobicyclic” ring structurecomprises 2 fused or bridged rings having ring members independentlyselected from carbon and one or more heteroatoms, including oxygen,nitrogen, phosphorous and/or sulfur. The heterobicyclic ring structurecan be saturated or unsaturated. The heterobicyclic ring can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position. The individual ringsmay or may not be of the same type. Examples of heterobicyclic ringstructures include octahydropyrrolo[3,4-c]pyrrole anddiazabicyclo[3.3.1]nonane and isobenzofuran.

Unless otherwise specifically defined, a “heterocyclic” ring is asaturated or unsaturated ring structure having about 3 to about 8 ringmembers independently selected from carbon atoms and one or moreheteroatoms, including oxygen, nitrogen, phosphorous and/or sulfur; forexample, azetidine, piperidine, morpholine, piperazine, (S) and(R)-1,2-dimethylpiperazine, 1-H-pyridine-2-one, dihydropyridine,tetrahydropyridine, pyridazin-3(2H)-one, piperidine-2,4-dione,pyrrolidine, thiomorpholine, 1,1-dioxothiomorpholine,tetrahydro-2H-thiopyran 1,1-dioxide, nucleosides and their derivatives.The heterocyclic ring can be unsubstituted, singly substituted or, ifpossible, multiply substituted, with substituent groups in any possibleposition.

Unless otherwise specifically defined, a “heterotricyclic” ringstructure comprises 3 fused, bridged, or both fused and bridged ringshaving ring members independently selected from carbon and one or moreheteroatoms, including oxygen, nitrogen, phosphorous and/or sulfur. Theheterotricyclic ring structure may be saturated or unsaturated. Theheterotricyclic ring structure can be unsubstituted, singly substitutedor, if possible, multiply substituted, with substituent groups in anypossible position. The individual rings may or may not be of the sametype. Examples of heterotricyclic ring structures include carbazole,phenanthroline, phenazine, 2,4,10-trioxaadamantane andtetradecahydro-phenanthroline.

Unless otherwise specifically defined, a “heteropolycyclic” ringstructure comprises more than 3 rings that may be fused, bridged or bothfused and bridged and that have ring members independently selected fromcarbon and one or more heteroatoms, including oxygen, nitrogen,phosphorous and/or sulfur. The heteropolycyclic ring structure can besaturated or unsaturated. The heteropolycyclic ring structure can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position. The individual ringsmay or may not be of the same type. Examples of heteropolycyclic ringstructures include azaadamantane, oxa-adamantine, tropane, homotropaneand 5-norbornene-2,3-dicarboximide.

Unless otherwise specifically defined, the term “phenacyl” refers to thegeneral formula phenylacyl.

Unless otherwise specifically defined, a “polycyclic” ring structurecomprises more than 3 rings that may be fused, bridged or both fused andbridged, and that includes carbon as ring atoms. The polycyclic ringstructure can be saturated or unsaturated. The polycyclic ring structurecan be unsubstituted, singly substituted or, if possible, multiplysubstituted, with substituent groups in any possible position. Theindividual rings may or may not be of the same type. Examples ofpolycyclic ring structures include adamantane, oxa-adamantane,bicyclooctane, norbornane and bicyclononanes.

Unless otherwise specifically defined, a glycol is an alcohol containingcompound with two hydroxyl groups. The glycol group can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position. Examples of glycolinclude 1,2-ethanediol, 1,3-propanediol and 1,4-butanediol.

Unless otherwise specifically defined, a polyol is an alcohol containingcompound more than two hydroxyl groups. The polyol group can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position.

Unless otherwise specifically defined, “PEG”, “PEG_(n)”, “PEG_(r)”, and“PEG_(s)” independently refer to the polyether entity tethered orconjugated to the compounds directly, via an alkyl group or via anotherlinker to improve the physicochemical properties such as watersolubility of the compounds. “PEG”, “PEG_(n)”, “PEG_(r)”, and “PEG_(s)”can be represented by the formula —(CH₂—CH₂—O—)_(m)CH₃ where m is 1-15.Examples of a linker are the amide group, carbamate, carbonate and theester group. The linker can be hydrolyzed physiologically orenzymatically. The definitions and immediate applications of the PEGtechnology can be adapted from Valentino J. Stella (editor), Prodrugs:Challenges and Rewards, 2007, Springer (volumes 1 and 2); hereinincorporated by reference in its entirety.

Unless otherwise specifically defined, the term “cannabinergic” refersto being related to the endocannabinoid system comprising of CB1 and CB2receptors and additionally the orphan receptors GPR55 and GPR119.

Unless otherwise specifically defined, the term “related analogs” refersto compounds disclosed in the technology that have the same propertiesas cannabinergic nitrate esters. For example, the related analogs bindcovalently to the cannabinoid receptors and/or can act as nitric oxidedonors while behaving as cannabinergic agonists, antagonists, partialagonists or allosteric modulators.

Unless otherwise specifically defined, the term “dual functionalbehavior” refers to compounds disclosed in the technology that have morethan one kind of an effect as shown in a standard in vitro assay. Forexample, a compound of the present technology can behave as a CB1antagonist as well as a CB2 agonist. The standard in vitro assay can beone or more selected from the cAMP accumulation assay, GTP-γS bindingassay, cell impedance assay, calcium mobilization assay or theβ-arrestin recruitment assay. In some instances, a compound disclosed inthe invention can behave as an orthosteric ligand, allosteric ligand ora biotopic ligand for the cannabinoid receptors. Unless otherwisespecifically defined, an orthosteric ligand binds to an orthosteric sitewhich refers to the endogenous agonist-binding site on a receptor.Unless otherwise specifically defined, an allosteric ligand binds to anallosteric site which refers to a binding site on the receptor that istopographically distinct from the endogenous agonist-binding(orthosteric) site. Bitopic ligands that have both orthostericligand-binding properties as well as a secondary element that is able tobind to a neighbouring allosteric site on the receptor. (Annu RevPharmacol Toxicol. 2012; 52:153-78, Nat Rev Drug Discov. 2013;12(1):25-34, Annu Rev Pharmacol Toxicol. 2013; 53:531-56; hereinincorporated by reference in its entirety).

Unless otherwise specifically defined, the term “nitric oxide donor”refers to compounds that can donate nitric oxide (NO). In someinstances, the term “nitric oxide donor” is used to designate a chemicalentity with the potential to elicit a NO(-like) response in livingsystems. Such compounds need not, in a literal sense, donate (or evenspontaneously evolve) bioactive NO under physiological conditions.

Unless otherwise specifically defined, the term “bind covalently tocannabinoid receptors” and “label the cannabinoid receptors” refers tothe cannabinoid receptors being temporarily or permanently modified. Themodification happens when a chemical species belonging to the compoundsattaches itself to the amino acid residues such as serines and cysteinesof the cannabinoid receptors via a covalent bond.

Unless otherwise specifically defined, the term “agonist” refers to acompound which decreases the cAMP levels; an “antagonist” or “neutralantagonist” has no effect on cAMP levels; a “partial agonist” inducessub-maximal decrease in cAMP levels; and an “inverse agonist” increasesthe cAMP levels.

Unless otherwise specifically defined, the term “physicochemicalproperties” refers to certain physical and chemical descriptiveproperties that the compounds possess. For example, compound 1 has abetter ClogP (octanol-water partition coefficient) and tPSA (total polarsurface area) value of 4.2 and 90.5 respectively as compared to Δ⁹-THCwhich has a ClogP and tPSA of 7.2 and 29.4.

Unless otherwise specifically defined, a “spirocyclic” ring is anon-aromatic ring structure wherein two rings are fused at one carbonatom and each ring can have 3 to 6 ring members independently selectedfrom carbon atoms and one or more heteroatoms, including oxygen,nitrogen, phosphorous and/or sulfur or a combination thereof and S canexist as S, SO or SO₂. Examples include azaspiro[3.3]heptane,azaspiro[3.5]nonane, spiro[3.3]heptane, azaspiro[5.5]undecane,azaspiro[3.4]octane, azaspiro[2.4]heptane, diazaspiro[4.5]decane,diazaspiro[3.5]nonane, diazaspiro[3.3]heptane, diazaspiro[4.4]nonane,diazaspiro[6.6]tridecane, thia-6-azaspiro[3.3]heptane,dioxo-thia-6-azaspiro[3.3]heptane, oxa-6-azaspiro[3.3]heptane.

Unless otherwise specifically defined, a tricyclic ring structurecomprises 3 rings that may be fused, bridged or both fused and bridged,and that includes carbon as ring atoms. The tricyclic ring structure canbe saturated or unsaturated. The tricyclic ring structure can beunsubstituted, singly substituted or, if possible, multiply substituted,with substituent groups in any possible position. The individual ringsmay or may not be of the same type. Examples of tricyclic ringstructures include fluorene and anthracene.

In general, “substituted” or “optionally substituted” refers to groups(e.g., an alkyl group, an aryl group) in which one or more bonds to ahydrogen atom contained therein may be replaced by a bond tonon-hydrogen or non-carbon atoms. As used herein, and unless otherwiseexcluded, any alkyl, alkenyl, alkynyl, alkenylene, carbocyclyl, aryl,heteroaryl, cyclyl, or heterocyclyl may be substituted. Substitutedgroups also include groups in which one or more bonds to a carbon(s) orhydrogen(s) atom are replaced by one or more bonds, including double ortriple bonds, to a heteroatom. Thus, a substituted group will besubstituted with one or more substituents, unless otherwise specified.In some embodiments, a substituted group is substituted with 1, 2, 3, 4,5, or 6 substituents. Substituent groups for the above moieties usefulin the technology are those groups that do not significantly diminishthe biological activity of the compound. Examples of substituent groupsinclude, but are not limited to, alkyl, alkynyl, alkenyl, alcohol,halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy,alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxygroups; carbonyls (oxo); carboxyls; esters; urethanes; oximes;hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides;sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides;hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines;guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates;thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like.In some embodiments, suitable substituents also include, terpene,boronic acid, boronate ester, BF₃K, biotin group tethered via an amidebond (e.g., alkyl, alkoxy or another linker attached to biotin via anamide bond), CF₂, CF₃, CF₂H, N₃, NCS, CN, NQ¹Q², ═O, OQ³, SQ³, NHQ³,═CH₂, ═NOH, OAc, O-acyl, O-aryl, CH₂-aryl, O-aroyl, NH-acyl, NH-aroyl,CHO, C(halogen)₃, (halogen)₂, COOQ³, SO₂-halogen, OSO₂CF₃, SO₃H,SO₃alkyl, SO₂NQ¹Q², CONQ¹Q², ═CH₂, OH, alkyl-OH, OH, ONO₂, alkyl-ONO₂,spirocyclic, alkylmercapto, aryl, aroyl, alkylamino, di-alkylamino,polycyclic, carbocyclic group, heterocyclic ring, aromatic ring,heteroaromatic ring, CO-T¹, —C(O)OP(O)(Oalkyl)₂, O—PO(OX¹)(OY¹),O-alkyl-(CH₂)_(p)—O—PO(OX¹)(OY¹) wherein p is 0-6, OSO₃H,OCO-alkyl-COOH, OCO-alkenyl-COOH, OPO₃H₂, O—SO₂alkyl-T¹, O—SO₂-T¹, OT¹,Oalkyl-T¹, NHSO₂-T¹, Nalkyl-SO₂-T¹, —O-COalkyl-T¹, NHCO-T¹, OCONH-T¹,O—CO-T¹, O—CO—O-T¹, OCO-alkyl-NH-T¹, OCO-alkyl-N(T¹)₂, OCO-alkyl-T¹,O-alkyl-T¹, O-alkyl-OCO-T¹, O-T¹-T¹, O-alkyl-PO(OX¹)(OY¹), OCO(glycol),OCO-alkyl(glycol), OCO-PEG_(r), O—CO—O-PEG_(r), O—COCO—O-PEG_(r), andO-PEG_(r); wherein

T¹ is H, alkyl, halogen, OH, CF₃, CF₂H, COOH, COOalkyl, alkaloid,immunogen, terpene, O—PO(OX¹)(OY¹), SO₃H, ONO₂ a heterocyclic ring,NQ¹Q² or T¹ is an ammonium group, wherein said ammonium group can beindependently substituted one or more times with a C1 to C6 alkylradical, or is a C3 to C7 heterocycle containing a nitrogen heteroatomfor bond formation, wherein the said heterocycle can contain one or moreheteroatoms independently selected from N, O or S, and wherein saidheterocycle can be substituted with one or more independently chosensubstituents;

-   -   r is 0 to 10;    -   wherein any of the above groups can be optionally substituted in        any possible position;    -   Q¹ and Q² are each independently H, alkyl, or alkyl-ONO₂, or    -   Q¹ and Q² together are part of a heterocyclic ring having about        4 to about 7 ring members and optionally one additional        heteroatom selected from O, N or S, or    -   Q¹ and Q² together are part of an imide ring having about 5 to        about 6 members;    -   Q³ is H, alkyl, heterocyclic ring, aromatic ring, heteroaromatic        ring hydroxyloweralkyl, or alkyl-NQ¹Q²;    -   X¹ and Y¹ are independently H, alkyl-OCO-alkyl,        alkyl-O—CO—O-alkyl, alkali metals or alkaline earth metals; and    -   PEG_(r) refers to a polyether PEGylated group tethered via a        linker.

The term “group comprising ONO₂” as used herein includes any moietyhaving a terminal —ONO₂ group. Such moieties include, but are notlimited to, ONO₂, alkyl-ONO₂, O-alkyl-ONO₂, O—SO₂-alkyl-ONO₂,—C(O)O-alkyl-ONO₂, alkyl-C(O)O-alkyl-ONO₂, alkyl-O-alkyl-ONO₂, and thelike. In some embodiments, the alkyl group is substituted with one ormore groups selected from hydroxyl, carboxyl, carboalkoxy, amide, amino,cycloalkyl, aryl, heteroaryl, or heterocyclyl groups.

In various embodiments, the compounds disclosed herein may suitablyinclude isomers, pharmaceutically acceptable salts, solvates, hydrates,amides, esters, ethers, chemically protected forms, tautomers,polymorphs and prodrugs thereof.

The term “composition(s) of the technology” as used herein meanscompositions comprising any of compounds described herein, such as forexample, compounds of formulae (I) (IX), or salts, tautomeric forms,hydrates, and solvates thereof.

The term “method(s) of the technology” as used herein means methodscomprising treatment with the compounds and/or compositions of thetechnology.

The term “solvate” as used herein means a compound, or apharmaceutically acceptable salt thereof, wherein molecules of asuitable solvent are incorporated in the crystal lattice. A suitablesolvent is physiologically tolerable at the dosage administered.Examples of suitable solvents are ethanol, water and the like. Whenwater is the solvent, the molecule is referred to as a “hydrate.”

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein, or pharmaceutically acceptable salts,tautomers, solvates, or hydrates thereof, with other chemicalcomponents, such as physiologically acceptable carriers and excipients.The purpose of a pharmaceutical composition is to facilitateadministration of a compound to an organism.

The term “pharmaceutically acceptable” refers to safe and non-toxic forin vivo, preferably, human administration.

The term “pharmaceutically acceptable salt” is intended to include saltsderived from inorganic or organic acids including, for example,hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric,formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic,salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic,trifluroacetic, trichloroacetic, naphthalene-2 sulfonic, oxalic,propionic, and other acids. Salts may also exist as solvates orhydrates. Other exemplary pharmaceutically acceptable salts aredescribed herein.

The term “acid” contemplates all pharmaceutically acceptable inorganicor organic acids. Inorganic acids include mineral acids such ashydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuricacids, phosphoric acids and nitric acids. Organic acids include allpharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylicacids, dicarboxylic acids, tricarboxylic acids, and fatty acids.Preferred acids are straight chain or branched, saturated or unsaturatedC1-C20 aliphatic carboxylic acids, which are optionally substituted byhalogen or by hydroxyl groups, or C6-C12 aromatic carboxylic acids.Examples of such acids are carbonic acid, formic acid, fumaric acid,acetic acid, propionic acid, isopropionic acid, valeric acid,alpha-hydroxy acids, such as glycolic acid and lactic acid, chloroaceticacid, benzoic acid, methane sulfonic acid, and salicylic acid. Examplesof dicarboxylic acids include oxalic acid, malic acid, succinic acid,tataric acid and maleic acid. An example of a tricarboxylic acid iscitric acid. Fatty acids include all pharmaceutically acceptablesaturated or unsaturated aliphatic or aromatic carboxylic acids having 4to 24 carbon atoms. Examples include butyric acid, isobutyric acid,sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid,linoleic acid, linolenic acid, and phenylsteric acid. Other acidsinclude gluconic acid, glycoheptonic acid and lactobionic acid.

As used herein the term “about” is used herein to mean approximately,roughly, around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of (+) or (−) 20 percent,10 percent, 5 percent or 1 percent.

An “effective amount”, “sufficient amount” or “therapeutically effectiveamount” as used herein is an amount of a compound that is sufficient toeffect beneficial or desired results, including clinical results. Assuch, the effective amount may be sufficient, for example, to reduce orameliorate the severity and/or duration of an affliction, or one or moresymptoms thereof, prevent the advancement of conditions related to anaffliction, prevent the recurrence, development, or onset of one or moresymptoms associated with an affliction, or enhance or otherwise improvethe prophylactic or therapeutic effect(s) of another therapy. Aneffective amount also includes the amount of the compound that avoids orsubstantially attenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results may include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminution of extent of disease, a stabilized (i.e., notworsening) state of disease, preventing spread of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

The term “in need thereof” refers to the need for symptomatic orasymptomatic relief from a condition.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which a compound is administered. Non-limiting examples of suchpharmaceutical carriers include liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical carriers may also be saline, gum acacia, gelatin,starch paste, talc, keratin, colloidal silica, urea, and the like. Inaddition, auxiliary, stabilizing, thickening, lubricating and coloringagents may be used. Other examples of suitable pharmaceutical carriersare described in “Remington's Pharmaceutical Sciences” by E. W. Martin(herein incorporated by reference in its entirety).

As used herein, the terms “animal,” “subject” and “patient” as usedherein include all members of the animal kingdom including, but notlimited to, mammals, animals (e.g., cats, dogs, horses, swine, etc.) andhumans. In some embodiments, an “individual” refers to a human. In someembodiments, an “animal” refers to, for example, nonhuman-primates suchas monkeys and baboons; veterinary animals, such as rodents, dogs, cats,horses and the like; and farm animals, such as cows, pigs and the like.In some embodiments, the subject or patient is a human.

In one aspect, novel cannabinergic nitrate esters (CNE) and relatedanalogs are provided. The cannabinergic nitrate ester compounds have arange of useful medical applications by acting as agonists, partialagonists, neutral antagonists, inverse-agonists or allosteric modulatorsfor the CB1, CB2 receptors and/or the GPR55 receptor. In someembodiments, the compounds exhibit dual functional behavior. In anotheraspect combination therapy, pharmaceutical preparations, andcompositions employing the CNE analogs are provided. In yet anotheraspect, methods of administering therapeutically effective amounts ofthe CNE analogs to provide a physiological effect are provided.

In certain aspects, the technology relates to new cannabinergic nitrateester compounds. Such compounds may act as nitric oxide donors; bindcovalently to and/or label the CB1, CB2 receptors and/or the GPR55receptor; act as agonists, partial agonists, neutral antagonists,inverse-agonists or allosteric modulators for the CB1, CB2 receptorsand/or the GPR55 receptor; have a predictable onset and duration ofaction; and/or have improved physicochemical properties.

The cannabimimetic nitrate esters can be represented by general formulaeI-IX; and encompasses all isomers including enantiomers, diastereomers,geometric isomers, racemates, tautomers, rotamers, and atropisomers,N-oxides, salts, solvates, and/or hydrates, metabolites andpharmaceutically acceptable salts. In general, the compositions of thetechnology may be alternately formulated to comprise, consist of, orconsist essentially of, any appropriate components herein disclosed. Thecompositions of the technology may additionally, or alternatively, beformulated so as to be devoid, or substantially free, of any components,materials, ingredients, adjuvants or species or that are otherwise notnecessary to the achievement of the function and/or objectives of thepresent technology.

In certain aspects, compounds of formula (I), isomers thereof orpharmaceutically acceptable salts thereof, are provided:

wherein

C has zero, one, two or three double bonds, and if present, at least onedouble bond is preferably in the C8-C9 position, the C9-C10 position, orthe C6a-C10a position;

wherein A, B and C are optionally substituted in any possible position;

X is C, CH, C(CH₂)₂, N, S, O, SO, or SO₂;

wherein when X is C, N or CH,

R¹ is (CH₂)_(p)— R⁶ wherein p=0-6;

-   -   R⁶ is H, alkyl, alkynyl, alkenyl, halogen, alcohol, alkoxy,        C(halogen)₂H, N₃, NCS, CN, NQ¹Q², ═O, ═CH₂, F₂, OQ³, SQ³, NHQ³,        ═NOH, OAc, O-acyl, O-aryl, 0-aroyl, NH-acyl, NH-aroyl, CHO,        C(halogen)₃, COOQ³, SO₂-halogen, OSO₂CF₃, SO₃H, SO₃alkyl,        SO₂NQ¹Q², CONQ¹Q², ONO₂, alkyl-T¹, alkenyl-T¹, alkynyl-T¹,        carbocyclic-T¹, spirocyclic, alkyl-ST¹, aroyl, alkylamino,        di-alkylamino, heterocyclic ring, carbocyclic group, aromatic        ring, heteroaromatic ring, CO-T¹, O—PO(OX¹)(OY¹),        O-alkyl-(CH₂)_(r)—O—PO(OX¹)(OY¹), OSO₃H, OCO-alkyl-COOH,        OCO-alkenyl-COOH, OPO₃H₂, O—SO₂alkyl-T¹, O—SO₂-T¹, OT¹,        NHSO₂-T¹, Nalkyl-SO₂-T¹, NHCO-T¹, OCONH-T¹, O—CO-T¹, O—CO—O-T¹,        OCO-alkyl-NH-T¹, OCO—NH-alkyl-T¹, OCO-alkyl-N(T¹)₂,        OCO-alkyl-T¹, O-alkyl-T¹, O-alkyl-OCO-T¹, O-T¹-T¹,        O-alkyl-PO(OX¹)(OY¹), OCO(glycol), OCO-alkyl(glycol),        OCO(polyol), OCO-alkyl(polyol), OCO-alkyl(BT), OCO-PEG_(r),        O—CO—O-PEG_(r), O—COCO—O-PEG_(r), or O-PEG_(r); wherein

T¹ is H, alkyl, halogen, OH, CF₃, CF₂H, COOH, COOalkyl, carbocyclicgroup, aromatic ring, heteroaromatic ring, alkaloid, terpene, immunogen,O—PO(OX¹)(OY¹), SO₃H, ONO₂ a heterocyclic ring, NQ¹Q² or T¹ is anammonium group, wherein said ammonium group can be independentlysubstituted one or more times with a C1 to C6 alkyl radical, or is a C3to C7 heterocycle containing a nitrogen heteroatom for bond formation,wherein the said heterocycle can contain one or more heteroatomsindependently selected from N, O or S, and wherein said heterocycle canbe substituted with one or more independently chosen substituents;

r is 0 to 10;

wherein any of the above groups can be optionally substituted in anypossible position;

Q¹ and Q² each independently are H or alkyl, alkyl-ONO₂; or

Q¹ and Q² together are part of a heterocyclic ring having about 4 toabout 7 ring members and optionally one additional heteroatom selectedfrom O, N or S; or

Q¹ and Q² together are part of an imide ring having about 5 to about 6members;

Q³ is H, alkyl, heterocyclic ring, aromatic ring, heteroaromatic ring,hydroxyloweralkyl, —P(O)(Oalkyl)₂ or alkyl-NQ¹Q²;

X¹ and Y¹ are H, alkyl-OCO-alkyl, alkyl-O—CO—O-alkyl, alkali metals oralkaline earth metals;

BT is a Biotin group tethered via an amide bond; and

PEG_(r) refers to a polyether PEGylated group tethered via a linker;

W is C(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂, C(CH₂)₂, spirocyclic ring,S, SO, SO₂, or C[CH₃(R⁴)];

Z is a bond, O, S, SO, SO₂, NH, N—CN or N-alkyl;

R⁴ is CH₂R⁵, C═(CH₂)_(n)—R⁵, or C(CH₂)_(n)—R⁵;

n=0 or 1;

R⁵ is alkyl, alkenyl, alkynyl, H, OH, N₃, NCS, ONO₂, CHO, halogen, COOH,COOalkyl, CONHalkyl, heterocyclic ring, or heteroaromatic ring;

R² is H, OH, SH, NH₂, CF₃, COOH, alkyl-OH, halogen, NHCOalkyl, NHalkyl,N(dialkyl), OC(S)N(dialkyl), NHSO₂alkyl, SC(O)N(dialkyl),O—PO(OX¹¹)(OY¹¹), O-alkyl-(CH₂)_(s)—O—PO(OX¹¹)(OY¹¹),O-alkyl-(CH₂)_(s)—C(O)O—PO(OX¹¹)(OY¹¹), OSO₃H, OCO-alkyl-COOH,OCO-alkenyl-COOH, OPO₃H₂, OSO₂alkyl-T¹¹, O—SO_(z) T¹¹, OT¹¹, NHCO-T¹¹,CONH-T¹¹, alkyl-T¹¹, OCONH-alkyl-T_(H), —O-COalkyl-T¹¹, OCONH-T¹¹,O—CO-T¹¹, O—CO—O-T¹¹, OCO-alkyl-NH-T¹¹,OCO-alkyl-N(T¹¹)₂O-alkyl-OCO-T¹¹, O-T¹¹-O-alkyl-PO(OX¹¹)(OY¹¹),OCO(glycol), OCO-alkyl(glycol), OCO(polyol), OCO-alkyl(polyol),OCOalkyl(BT), OCO-PEG_(s), O—CO—O—PEG_(s), O—COCO—O—PEG, O-PEG_(s);

T¹¹ is H, alkyl, carbocylic group, halogen, OH, NO₂, ONO₂, CF₃, CF₂H,COOH, COOalkyl, alkaloid, terpene, immunogen, O—PO(OX¹¹)(OY¹¹), SO₃H,N₃, NCS, aromatic ring, heteroaromatic ring, a heterocyclic ring, orNQ¹¹Q¹², or T¹¹ is an ammonium group, wherein said ammonium group can beindependently substituted one or more times with a C1 to C6 alkylradical, or is a C3 to C7 heterocycle containing a nitrogen heteroatomfor bond formation, wherein the said heterocycle can contain one or moreheteroatoms independently selected from nitrogen, oxygen or sulfur, andwherein said heterocycle can be substituted with one or moreindependently chosen substituents;

s is 0 to 10;

X¹¹ and Y¹¹ are H, alkyl, alkyl-OCO-alkyl, alkyl-O—CO—O-alkyl, alkalimetals or alkaline earth metals;

Q¹¹ and Q¹² are each independently H or alkyl, or

Q¹¹ and Q¹² together are part of a heterocyclic ring having about 4 toabout 7 ring members and optionally one additional heteroatom selectedfrom O, N or S, or

Q¹¹ and Q¹² together are part of an imide ring having about 5 to about 6members;

Q¹³ is H, alkyl, hydroxyloweralkyl, or alkyl-NQ¹¹Q¹²;

BT is a Biotin group tethered via an amide bond; and

PEG_(s) refers to a polyether PEGylated group tethered via a linker;

Y is a bond, C(CH₃)₂, C(halogen)₂, C═O, C(alkyl), C(carbocyclic),C(heterocyclic), COO, NHCO, CONH, alkyl, cycloalkyl, heterocyclic ring,a lactone, lactam, sultam, O, S, SO, SO₂, OSO₂, NH, N-alkyl, a carbonatom directly as part of R³, N═N, CH═CH, CH═ or C≡C;

R³ is -D¹-J¹-J²;

D¹ is a bond or an optionally substituted alkyl group, alkenyl group,alkenylene, alkynyl group, cycloalkyl, a carbocyclic group, aspirocyclic ring, a polycyclic ring, a heterocyclic ring, an aromaticring, a heteroaromatic ring, C═O(O), O(C═O), CONH, NHCO, O, S, SO₂,SO₂NH, NHSO₂, NH(alkyl), N(alkyl), NH, or OSO₂; and

J¹ and J² are absent or are each independently selected from alkyl, O,NH, N, COO, OCO, O—CO—O, CONH, CONHalkyl, NHCO, NHCOalkyl, OSO₂, SO₂NH,and NHSO₂;

V is V¹ when either A, B or C are substituted with a group comprisingONO₂, or V is ONO₂;

V¹ is H, halogen, CF₃, CF₂H, N₃, NCS, CN, NO₂, NX¹X²OX³, SX³, OAc,OSO₂X³, O-acyl, S-acyl, SO₂-alkyl, SO-alkyl, SC(CH₃)₂COOX⁸,OC(CH₃)₂COOX⁸, C(CH₃)₂COOX⁸, Si(alkyl)₃, alkyl-CN, O-aroyl,O(CH₂)_(j)OX³, O(CH₂)_(j)NX¹X², NH-acyl, NH-aroyl, CHO, C(halogen)₃,COOX³, COOX⁷, SO₃H, SO₂NX¹X², CONX¹X², NHC(O)O-alkyl, NHSO2-alkyl,alkoxy, alkyl, alkenyl group, alkenylene, alkynyl group, cycloalkyl, acarbocyclic group, a spirocyclic ring, a polycyclic ring, a heterocyclicring, an aromatic ring, a heteroaromatic ring, alcohol, alkylmercapto,alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, boronic acid,boronate ester, BF₃K, biotin group tethered via an amide bond, CX⁴X⁵X⁶,—CH═CHX⁸, —C≡CX⁸;

X¹ and X² each independently comprise H or alkyl, or

X¹ and X² together comprise part of a heterocyclic ring having about 4to about 7 ring members and optionally one additional heteroatomselected from O, N or S, or

X¹ and X² together comprise part of an imide ring having about 5 toabout 6 members,

X³ comprises H, alkyl, aryl, NO₂, (CH₂)_(m)CN, hydroxyloweralkyl, oralkyl-NX¹X²,

X⁴, X⁵, and X⁶ each independently comprise H, alkyl, carbocyclic group,hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO₂)alkyl, NX¹X²,COOX³, CONX³, OX⁷, or O-alkyl-X⁷ wherein

X⁷ comprises H, alkyl, NO₂, NO, P(O)(OX⁸)₂, PH(O)(OX⁸),S(O)_(k)N(alkyl)₂, S(O)_(k)X⁸, S(O)_(k)OX⁸, COOX⁸, CONX⁸, SO₃H, COX⁸,wherein

X⁸ comprises H, alkyl, carbocyclic group, heterocyclic ring, aromaticring, heteroaromatic ring, or —CX⁹═CHX¹⁰ wherein

X⁹ and X¹⁰ each independently comprise H or alkyl

m is an integer from 0 to 7

j is an integer from 0 to about 6, and

k is an integer from 0 to about 2.

In some embodiments, C has zero, one, two or three double bonds, and ifpresent, at least one double bond is in the C8-C9 position, the C9-C10position, or the C6a-C10a position;

wherein A, B and C are optionally substituted in any possible position;

X is C, CH, (CH₂)₂, or N;

wherein when X is C, N or CH,

R¹ is (CH₂)_(p)— R⁶ wherein p=0-2;

R⁶ is H, alkyl, alkynyl, alkenyl, alcohol, alkoxy, ═O, ONO₂, alkyl-ONO₂,heteroaromatic ring, or COOH;

W is C(CH₃)₂, CH(CH₃), C═O, or CF₂;

Z is O, NH, or N-alkyl;

R² is H, OH, Oalkyl-T¹¹, alkyl-T¹¹, —O-COalkyl-T¹¹, O—CO-T¹¹,OCO-alkyl-NH-T¹¹, or OCO-alkyl-N(T¹¹)₂;

wherein, T¹¹ is H, alkyl, ONO₂, or a heterocyclic ring;

Y is C(CH₃)₂, C(halogen)₂, CH(alkyl), alkyl, or O;

R³ is D¹-J¹-J²;

D¹ is an alkyl group, alkenyl group, alkynyl group, or CO₂-alkyl; or apharmaceutically acceptable salt thereof; and

V is H when R⁶ or is ONO₂, or V is ONO₂.

In certain aspects, compounds of formula (I), isomers thereof orpharmaceutically acceptable salts thereof, are provided:

wherein

A is an optionally substituted aromatic ring, heteroaromatic ring,heterocyclic ring, quinone, alkaloid, terpene or a related derivative;

W is absent, or is C(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂, C(CH₂)₂,spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)];

Z is absent or is a bond, OH, O, S, N, SO, SO₂, NH, N—CN or N-alkyl; and

remaining variables are are as previously defined.

In some embodiments, C is selected from the group consisting of:

In some embodiments, B is selected from the group consisting of:

In some embodiments, A is selected from the group consisting of:

In some embodiments, compounds of formula (I), isomers thereof orpharmaceutically acceptable salts thereof, are provided:

wherein:

C has zero, one, two or three double bonds;

X is C, CH, N, NH, (CH₂)₂N, S, O, SO, SO₂, or CF₂;

R¹ is H, OH, ═O, halogen, COOH, nitro, ONO₂, or optionally substitutedalkyl, haloalkyl, alkenyl, alkynyl, acyl, aryl, heterocyclyl,heteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, alkenyl,amino, thio, cyano, thiocynato, isothiocynato, carboxyl, formyl,carbamyl, amino, acylamino, amido, imido, aminoalkyl, aminoaryl,heteroarylamino, heterocyclylamino, sulfonate, sufonamide, sulfonyl,thioalkyl, thioaryl, heteroarylthio, heterocyclylthio, phosphonate,phosphate and acetate group;

W is C(CH₃)₂, CH(CH₃), C═O, C(O)-alkyl, CF₂, C═S, C═CH₂, C(CH₂)₂,spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)];

R⁴ is an optionally substituted alkyl, alkenyl, or alkynyl group;

Z is O, S, SO, SO₂, NH, or N-alkyl;

R² is H, OH, SH, NH₂, CF₃, COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂, oroptionally substituted alkyl, haloalkyl, amine, amide, imide, alkoxy,alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl, amino,acylamino, amido, imido, aminoalkyl, aminoaryl, heteroarylamino,heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl, thioaryl,heteroarylthio, heterocyclylthio, phosphonate, phosphate or acetategroup;

Y is a bond, C(CH₃)₂, CF₂, C═O, C(alkyl), COO, NHCO, CONH, or optionallysubstituted alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O,S, SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynyl group;

R³ is absent, or is O, S, SO₂, SO₂NH, NHSO₂, or OSO₂ or is an optionallysubstituted alkyl, alkenyl, alkynyl, cycloalkyl, a carbocyclic, aspirocyclic, heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine,amide, imide groups; and

V is V¹ or ONO₂, wherein when A, B or C is substituted with a groupcomprising ONO₂ in any position, V is V¹, otherwise V is ONO₂.

In some embodiments, C has at least one double bond at the C8-C9position, the C9-C10 position, or the C6a-C10a position. In someembodiments, V is ONO₂. In some embodiments, R¹ is a group comprisingONO₂ and V is V¹. In some embodiments, R¹ is ONO₂, alkyl-ONO₂,O-alkyl-ONO₂, O—SO₂-alkyl-ONO₂, —C(O)O-alkyl-ONO₂,alkyl-C(O)O-alkyl-ONO₂, or alkyl-O-alkyl-ONO₂.

In some embodiments, C has one, two or three double bonds, and at leastone double bond is at the C8-C9 position, the C9-C10 position, or theC6a-C10a position; W is C(CH₃)₂, CH(CH₃), C═O, or CF₂; Z is O or N; andV is V¹ when R¹ is a group comprising ONO₂, or V is ONO₂. In someembodiments, Y—R³—V is ONO₂, alkyl-ONO₂, O-alkyl-ONO₂, O—SO₂-alkyl-ONO₂,—C(O)O-alkyl-ONO₂, alkyl-C(O)O-alkyl-ONO₂, or alkyl-O-alkyl-ONO₂.

In some embodiments of compound of formula (I), C is selected from thegroup consisting of:

In some embodiments of compound of formula (I), B is selected from thegroup consisting of:

In another embodiment, compounds of formula (II), isomers thereof orpharmaceutically acceptable salts thereof, are provided.

wherein,

C is optionally substituted alkyl, alkenyl, alkynyl, a carbocyclicgroup, bicyclic ring, aromatic ring, heterocyclic ring, heteroaromaticring, alkaloid, terpene or a related derivative;

G is optionally present and when present is a direct bond or a groupselected from C═O, NH, CH₂, CONH, NHCO, CONH(alkyl)-, COO, OCO, OCH₂,alkyl, S, SO, SO₂, and O;

A is an optionally substituted aromatic ring, heteroaromatic ring,heterocyclic ring, quinone, alkaloid, terpene or a related derivative;

R^(2a) and R^(2b) are each independently R²; and

R², R³, V and Y are as previously defined.

In some embodiments of compound of formula (II), C is selected from aring system comprising

In some embodiments of compound of formula (II), A is selected from aring system comprising

In yet another embodiment, compounds of formula (III), isomers thereofor pharmaceutically acceptable salts thereof, are provided.

wherein,

C is an optionally substituted carbocyclic group, bicyclic ring,aromatic ring, heterocyclic ring, heteroaromatic ring, alkaloid, terpeneor a related derivative;

R^(2a) and R^(2b) are each independently R²; and

R², R³, V and Y are as previously defined.

In some embodiments of the compound of formula (III), V is ONO₂.

In some embodiments of compound of formula (III), C is selected from aring system comprising

In some embodiments, compounds of formula (IV), isomers thereof orpharmaceutically acceptable salts thereof, are provided.

wherein,

C is optionally substituted alkyl, alkenyl, alkynyl, a carbocyclicgroup, bicyclic ring, aromatic ring, heterocyclic ring, heteroaromaticring, alkaloid, terpene or a related derivative;

R^(2a) and R^(2b) are each independently R²; and

R², R³, V and Y are as previously defined.

In some embodiments of compound of formula (IV), C is selected from aring system comprising

In some embodiments, compounds of formula (V), isomers thereof orpharmaceutically acceptable salts thereof, are provided.

wherein,

C has zero or one double bond, and if present, the double bond ispreferably in the C2-C3 position or C3-C4 position;

R^(2a) and R^(2b) are each independently R²; and

R¹, R², R³, V, X and Y are as previously defined.

In some embodiments, compounds of formula (VT), isomers thereof orpharmaceutically acceptable salts thereof, are provided.

wherein,

C has zero, one or three double bonds, and if present, at least onedouble bond is preferably in the C1-C2 position;

C8-C9 is a double bond and optionally a single bond;

R^(2a) and R^(2b) are each independently R²;

M is CH₂ or alkyl-T¹;

L is CH₃ or alkyl-T¹; and

R¹, R², R³, V, X and Y are as previously defined.

In some embodiments of compound of formula (VI), C is selected from aring system comprising

In some embodiments of compounds of formula (VII), isomers thereof orpharmaceutically acceptable salts thereof, are provided.

wherein,

C has zero, one or three double bonds;

P is H, alkyl-OH, C(CH₃)₂(T¹) or alkyl-ONO₂;

R^(2a) and R^(2b) are each independently R²; and

R¹, R², R³, V, X and Y are as previously defined.

In some embodiments of compound of formula (VII), C is selected from aring system comprising

In another embodiment, compounds of formula (VIII), isomers thereof orpharmaceutically acceptable salts thereof, are provided.

wherein,

C is an optionally substituted carbocyclic group, bicyclic ring,aromatic ring, heterocyclic ring,heteroaromatic ring, alkaloid, terpene or a related derivative;

G is a bond or a group selected from C═O, NH, CH₂, CONH, NHCO, S and O;

W is a bond, C(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂, C(CH₂)₂,spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)];

Z is O, S, SO, SO₂, NH, or N-alkyl; and

R², R³, R⁴, V and Y are as defined herein for formula (I).

In some embodiments, compounds of formula (IX), isomers thereof orpharmaceutically acceptable salts thereof, are provided.

wherein,

C is as defined previously for formulae (I-VIII) and

n=0, 1; and

R₂, R₃, V, W, Z, and Y are as defined herein for formula (I).

In some embodiments, C is aromatic and A is aromatic, and G is C═O;

C is aromatic and A is heteroaromatic, and G is C═O;C is aromatic and A is heteroaromatic, and G is CONH;C is heterocyclic and A is heteroaromatic, and G is C═O;C is heterocyclic and A is heteroaromatic, and G is C═O;C is alkyl and A is heteroaromatic, and G is C═O;C is carbocyclic and A is heteroaromatic, and G is C═O;C is alkyl, and A is heteroaromatic, and G is CONH;C is carbocyclic and A is heteroaromatic, and G is C═O;C is alkyl, and A is heteroaromatic, and G is CONH;C is heteroaromatic and A is heteroaromatic, and G is N(alkyl)SO₂;C is aromatic and A is heteroaromatic, and G is NH;C is bicyclic ring and A is aromatic, and G is O;C is bicyclic ring and A is aromatic, and G is a direct bond;C is a terpene;C is carbocyclic and W is optionally present;C is heteroaromatic and A is heteroaromatic, and G is OCH₂;C is heterocyclic and A is aromatic, and G is CH₂;C is aromatic and A is heterocyclic, and G is CH₂;C is carbocyclic and A is heteroaromatic, and G is a COO or OCO;C is heterocyclic and A is aromatic, and G is a direct bond;C is heterocyclic and A is heteroaromatic, and G is a direct bond;C is a terpene and A is aromatic, and G is a direct bond;C is a terpene and A is quinone, and G is a direct bond;C is a terpene and A is aromatic, and G is a direct bond;C is heterocyclic and A is aromatic, and G is a direct bond;C is aromatic and A is aromatic, and G is a direct bond;C is aromatic and A is heterocyclic, and G is a direct bond;C is alkyl and A is heteroaromatic, and G is a direct bond;C is a terpene and A is aromatic, and G is a direct bond;C is bicyclic and W is C═O; orC is carbocyclic, B is carbocyclic and A is aromatic.

In any of the above embodiments of Formula IX, C may be:

In some embodiments of the compound of formula (1), the compound has theformula (Ia):

wherein the substituents are as previously defined.

In some embodiments of formula (I) and (Ia), C is carbocyclic and W isC═O.

In some embodiments of formula (I) and (Ia), C is carbocyclic and W isC[CH₃(R⁴)].

In some embodiments of the compound of formula (II), C is an optionallysubstituted carbocyclic group, bicyclic ring, aromatic ring,heterocyclic ring, heteroaromatic ring, or a terpene;

A is an optionally substituted aromatic ring, heteroaromatic ring, orquinone;

G is a bond, C═O, NH, CH₂, or O; and

R^(2a) and R^(2b) are each independently R².

In some embodiments of the compound of formula (II), the compound hasthe formula (IIa):

wherein,

C is an optionally substituted carbocyclic group, bicyclic ring,aromatic ring, heterocyclic ring, heteroaromatic ring, or a terpene;

G is a bond or a group selected from C═O, NH, CH₂, CONH, NHCO, COO, OCO,OCH₂, S, SO, SO₂ and O;

A is an optionally substituted aromatic ring, heteroaromatic ring,heterocyclic ring, or quinone;

R^(2a) and R^(2b) are each independently R²; and

R², R³ and Y are as previously defined.

In some embodiments of formulae (II) or (IIa), C is aromatic and A isaromatic; and G is C═O.

In some embodiments of formulae (II) or (IIa), C is aromatic and A isheteroaromatic; and G is C═O.

In some embodiments of formulae (II) or (IIa), C is aromatic and A isheteroaromatic; and G is CONH.

In some embodiments of formulae (II) or (IIa), C is heterocyclic and Ais heteroaromatic; and G is C═O.

In some embodiments of formulae (II) or (IIa), C is alkyl and A isheteroaromatic; and G is C═O.

In some embodiments of formulae (II) or (IIa), C is heteroaromatic and Ais heteroaromatic; and G is N(alkyl)SO₂.

In some embodiments of formulae (II) or (IIa), C is aromatic and A isheteroaromatic; and G is NH.

In some embodiments of formulae (II) or (IIa), C is bicyclic ring and Ais aromatic; and G is O.

In some embodiments of formulae (II) or (1Ia), C is bicyclic ring and Ais aromatic; and G is a direct bond.

In some embodiments of formulae (II) or (IIa), C is heterocyclic and Ais aromatic; and G is CH₂.

In some embodiments of formulae (II) or (IIa), C is heterocyclic and Ais aromatic; and G is a direct bond.

In some embodiments of formulae (II) or (IIa), C is a terpene and A isaromatic; and G is a direct bond.

In some embodiments of formulae (II) or (IIa), C is a terpene and A isquinone; and G is a direct bond.

In some embodiments of formulae (II) or (IIa), C is a terpene and A isaromatic; and G is a direct bond.

In some embodiments of the compound of formula (III), the compound hasthe formula (IIIa):

wherein,

C is an optionally substituted carbocyclic group, bicyclic ring,aromatic ring, heterocyclic ring, heteroaromatic ring, or a terpene;

R^(2a) and R^(2b) are each independently R²; and

R², R³ and Y are as previously defined.

In some embodiments of formulae (III) or (IIIa), C is heterocyclic and Ais aromatic; and G is a direct bond.

In some embodiments of formulae (III) or (IIIa), C is a terpene and A isaromatic; and G is a direct bond.

In some embodiments of the compound of formula (IV), the compound hasthe formula (IVa):

wherein, C is an optionally substituted carbocyclic group, bicyclicring, aromatic ring, heterocyclic ring, heteroaromatic ring, or aterpene;

R^(2a) and R^(2b) are each independently R²; and

R², R³ and Y are as previously defined.

In some embodiments of formulae (IV) or (IVa), C is a terpene.

In some embodiments of formulae (IV) or (IVa), C is an aromatic ring.

In some embodiments of formulae (IV) or (IVa), C is carbocyclic.

In some embodiments of the compound of formula (V), the compound has theformula (Va):

wherein, C has within zero or one double bond, and if present, thedouble bond is preferably in the C2-C3 position or C3-C4 position;

R^(2a) and R^(2b) are each independently R²; and

R¹, R², R³, X and Y are as previously defined.

In some embodiments of the compound of formula (VI), the compound hasthe formula (VIa):

wherein, C has zero, one or three double bonds, and if present, at leastone double bond is preferably in the C1-C2 position;

C8-C9 is a double bond and optionally a single bond;

R^(2a) and R^(2b) are each independently R²; and

M is CH₂ or alkyl-T¹;

L is CH₃ or alkyl-T¹; and

R¹, R², R³, X and Y are as previously defined.

In some embodiments of the compound of formula (VII), the compound hasthe formula (VIIa):

wherein, C has zero, one or three double bonds;

P is H, alkyl-OH or alkyl-ONO₂;

R^(2a) and R^(2b) are each independently R²; and

R¹, R², R³, X and Y are as previously defined.

In some embodiments of the formula (VIII), the compound has the formula(VIIIa):

wherein,

C is an optionally substituted carbocyclic group, bicyclic ring,aromatic ring, heterocyclic ring, heteroaromatic ring, or a terpene;

G is a bond or a group selected from C═O, NH, CH₂, CONH, NHCO, S and O;

W is a bond, C(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂, C(CH₂)₂,spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)];

Z is O, S, SO, SO₂, NH, or N-alkyl

R², R³, R⁴ and Y are as defined herein for compounds of formula (I.

In some embodiments, C has zero double bonds. In some embodiments, C hasone double bond in the C8-C9 position, the C9-C10 position, or theC6a-C10a position. In some embodiments, C has two double bonds. In someembodiments, C has three double bonds.

In some embodiments, W is C(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂,C(CH₂)₂, spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)]. In someembodiments, W is a C(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂, C(CH₂)₂,spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)]. In some embodiments, W isC(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂, C(CH₂)₂, S, SO₂, or C[CH₃(R⁴)].In some embodiments, W is C(CH₃)₂, CH(CH₃), C═O, CF₂, C(CH₂)₂, S, orSO₂. In some embodiments, W is C(CH₃)₂, CH(CH₃), C═O, CF₂, or C(CH₂)₂.

In some embodiments, W is C(CH₃)₂, C═O, CF₂, or C(CH₂)₂. In someembodiments, W is C(CH₃)₂, C═O, CF₂, or C(CH₂)₂. In some embodiments, Wis C(CH₃)₂, C═O, or CF₂. In some embodiments, W is C(CH₃)₂ or CF₂. Insome embodiments, W is C(CH₃)₂. In some embodiments, W is CF₂.

In some embodiments, V is V¹ when A or C are substituted with a groupcomprising ONO₂, or V is ONO₂. In some embodiments, V is V′ when R⁶ orT¹¹ are ONO₂, or V is ONO₂. In some embodiments, V is H when R¹comprises ONO₂, or V is ONO₂. In some embodiments, V is V¹ when R¹comprises ONO₂ or P is ONO₂ or V is ONO₂. In some embodiments, V is H orONO₂. In some embodiments, V is H. In some embodiments, V is ONO₂.

In some embodiments, R⁴ is CH₂R⁵, C═(CH₂)_(n)—R⁵, or C≡(CH₂)_(n)—R⁵. Insome embodiments, R⁴ is CH₂R⁵ or C═(CH₂)_(n)—R⁵. In some embodiments, R⁴is CH₂R⁵ or C≡(CH₂)_(n)—R⁵. In some embodiments, R⁴ is C═(CH₂)_(n)—R⁵ orC4CH₂)_(n)—R⁵. In some embodiments, R⁴ is CH₂R⁵. In some embodiments, R⁴is C═(CH₂)_(n)—R⁵. In some embodiments, R⁴ is C(CH₂)_(n)—R⁵.

In some embodiments, n is 0 or 1. In some embodiments, n is 0. In someembodiments, n is 1.

In some embodiments, R⁵ is alkyl, alkenyl, alkynyl, H, OH, N₃, NCS,ONO₂, CHO, halogen, COOH, COOalkyl, CONHalkyl, heterocyclic ring, orheteroaromatic ring. In some embodiments, R⁵ is alkyl, alkenyl, alkynyl,OH, N₃, ONO₂, halogen, COOH, COOalkyl, CONHalkyl, heterocyclic ring, orheteroaromatic ring. In some embodiments, R⁵ is alkyl, ONO₂, halogen,heterocyclic ring, or heteroaromatic ring. In some embodiments, R⁵ isalkyl, heterocyclic ring, or heteroaromatic ring. In some embodiments,R⁵ is alkyl.

In some embodiments, X is C, CH, (CH₂)₂ N, S, O, SO, or SO₂. In someembodiments, X is C, CH, or (CH₂)₂. In some embodiments, X is C, CH, orN. In some embodiments, X is C or CH. In some embodiments, X is C. Insome embodiments, X is CH.

In some embodiments, p is 0-6. In some embodiments, p is 0-3. In someembodiments, p is 0-2. In some embodiments, p is 0-1. In someembodiments, p is 0. In some embodiments, p is 1.

6 In some embodiments, R H, alkyl, alkynyl, alkenyl, halogen, alcohol,alkoxy, CF₂H, N₃, NCS, CN, ONO₂, NQ¹Q², =0, 0Q³, SQ³, NHQ³, ═CH₂, OAc,O-acyl, O-aryl, O-aroyl, NH-acyl, NH-aroyl, C(halogen)₃, (halogen)₂,COOQ³, SO₂-halogen, OSO₂CF₃, SO₃H, SO₃alkyl, SO₂NQ¹Q², CONQ¹Q²,alkyl-OH, ONO₂, alkyl-ONO₂, spirocyclic, alkylmercapto, aroyl,alkylamino, di-alkylamino, heterocyclic ring, aromatic ring,heteroaromatic ring, CO-T¹, O—PO(OX¹)(OY¹),O-alkyl-(CH₂)_(r)—O—PO(OX¹)(OY¹), OSO₃H, OCO-alkyl-COOH,OCO-alkenyl-COOH, OPO₃H₂, O—SO₂alkyl-T¹, O—SO₂-T¹, OT¹, Oalkyl-T¹,NHSO₂-T¹, Nalkyl-SO₂-T¹, —O-COalkyl-T¹, NHCO-T¹, OCONH-T¹, O—CO-T¹,O—CO—O-T¹T¹, OCO-alkyl-N(T¹)₂, OCO-alkyl-T¹, O-alkyl-T¹, O-alkyl-OCO-T¹,O-T¹-T¹, O-alkyl-PO(OX¹)(OY¹), OCO(glycol), OCO-alkyl(glycol),OCO(polyol), OCO-alkyl(polyol), OCO-alkyl(BT), OCO-PEG_(r),O—CO—O-PEG_(r), O—COCO—O-PEG_(r), or O-PEG_(r).

In some embodiments, R⁶ is H, alkyl, alkynyl, halogen, alcohol, alkoxy,CN, CO₂H, ONO₂, ═O, ═CH₂, OAc, O-acyl, O-aryl, O-aroyl, NH-acyl,NH-aroyl, C(halogen)₃, (halogen)₂, alkyl-ONO₂, heterocyclic ring,aromatic ring, or heteroaromatic ring. In some embodiments, R⁶ is H,alkyl, alkynyl, alcohol, alkoxy, CO₂H, ONO₂, ═O, ═CH₂, heterocyclicring, aromatic ring, or heteroaromatic ring. In some embodiments, R⁶ isH, alkyl, alkynyl, alcohol, alkoxy, CO₂H, ONO₂, ═O, ═CH₂, heterocyclicring, aromatic ring, or heteroaromatic ring. In some embodiments, R⁶ isH, alkyl, alkynyl, alcohol, alkoxy, CO₂H, ONO₂, ═o, or ═CH₂.

In some embodiments, T¹ is H, alkyl, halogen, OH, CF₃, CF₂H, COOH,COOalkyl, O—PO(OX¹)(OY¹), SO₃H, ONO₂ a heterocyclic ring, NQ¹Q² or T¹ isan ammonium group, wherein said ammonium group can be independentlysubstituted one or more times with a C1 to C6 alkyl radical, or is a C3to C7 heterocycle containing a nitrogen heteroatom for bond formation,wherein the said heterocycle can contain one or more heteroatomsindependently selected from N, O or S, and wherein said heterocycle canbe substituted with one or more independently chosen substituents. Insome embodiments, T¹ is H, alkyl, CF₃, CF₂H, O—PO(OX¹)(OY¹), ONO₂ aheterocyclic ring, NQ¹Q² or T¹ is an ammonium group, wherein saidammonium group can be independently substituted one or more times with aC1 to C6 alkyl radical, or is a C3 to C7 heterocycle containing anitrogen heteroatom for bond formation, wherein the said heterocycle cancontain one or more heteroatoms independently selected from N, O or S,and wherein said heterocycle can be substituted with one or moreindependently chosen substituents. In some embodiments, T¹ is H, alkyl,a heterocyclic ring, or T¹ is an ammonium group, wherein said ammoniumgroup can be independently substituted one or more times with a C1 to C6alkyl radical, or is a C3 to C7 heterocycle containing a nitrogenheteroatom for bond formation, wherein the said heterocycle can containone or more heteroatoms independently selected from N, O or S, andwherein said heterocycle can be substituted with one or moreindependently chosen substituents. In some embodiments, T¹ is H, alkyl,or a heterocyclic ring. In some embodiments, T¹ is H or alkyl. In someembodiments, T¹ is H. In some embodiments, T¹ is alkyl.

In some embodiments, r is 0 to 10. In some embodiments, r is 0 to 6. Insome embodiments, r is 0 to 4. In some embodiments, r is 0 to 2. In someembodiments, r is 0 to 1. In some embodiments, r is 0. In someembodiments, r is 1.

In some embodiments, Q¹ and Q² each independently are H, alkyl oralkyl-ONO₂; or Q¹ and Q² together are part of a heterocyclic ring havingabout 4 to about 7 ring members and optionally one additional heteroatomselected from O, N or S. In some embodiments, Q¹ and Q² eachindependently are H, alkyl or alkyl-ONO₂; or Q¹ and Q² together are partof a heterocyclic ring having about 4 to about 7 ring members. In someembodiments, Q¹ and Q² each independently are H, alkyl or alkyl-ONO₂. Insome embodiments, Q¹ and Q² together are part of a heterocyclic ringhaving about 4 to about 7 ring members. In some embodiments, Q¹ and Q²each independently are H or alkyl. In some embodiments, Q¹ and Q² eachindependently are H or alkyl-ONO₂. In some embodiments, Q¹ and Q² eachindependently are alkyl or alkyl-ONO₂. In some embodiments, Q¹ and Q²are H. In some embodiments, Q¹ and Q² are alkyl. In some embodiments, Q¹and Q² are alkyl-ONO₂.

In some embodiments, X¹ and Y¹ are H, alkyl-OCO-alkyl, oralkyl-O—CO—O-alkyl. In some embodiments, X¹ and Y¹ are H oralkyl-OCO-alkyl. In some embodiments, X¹ is H, alkyl-OCO-alkyl,alkyl-O—CO—O-alkyl, alkali metal or alkaline earth metal. In someembodiments, X¹ is H, alkyl-OCO-alkyl, or alkyl-O—CO—O-alkyl. In someembodiments, X¹ is H. In some embodiments, Y¹ is H, alkyl-OCO-alkyl,alkyl-O—CO—O-alkyl, alkali metal or alkaline earth metal. In someembodiments, Y¹ is H, alkyl-OCO-alkyl or alkyl-O—CO—O-alkyl. In someembodiments, Y¹ is H.

In some embodiments, Y is C(CH₃)₂, CF₂, C(alkyl), COO, CONH, alkyl, O,S, SO, SO₂, OSO₂, NH, or N-alkyl. In some embodiments, Y is C(CH₃)₂,CF₂, COO, CONH, alkyl, O, OSO₂, NH, or N-alkyl. In some embodiments, Yis C(CH₃)₂, CH₂, CF₂, O, or OSO₂. In some embodiments, Y is C(CH₃)₂,CH₂, CF₂, or O. In some embodiments, Y is C(CH₃)₂, CH₂, or CF₂. In someembodiments, Y is C(CH₃)₂. In some embodiments, Y is CH₂. In someembodiments, Y is CF₂.

In some embodiments, Z is O, SO₂, NH, or N-alkyl. In some embodiments, Zis O, NH, or N-alkyl. In some embodiments, Z is O, or N-alkyl. In someembodiments, Z is O, or N-methyl. In some embodiments, Z is O. In someembodiments, Z is N-methyl. In some embodiments, Z and/or W are a bond.

In some embodiments, R² is H, OH, SH, CF₃, COOH, alkyl-OH, halogen,NHCOalkyl, NHalkyl, N(dialkyl), NHSO₂alkyl, OCO-alkyl-COOH,OCO-alkenyl-COOH, OSO₂alkyl-T¹¹, O—SO₂-T¹¹, OT¹¹, alkyl-T¹¹,—O-COalkyl-T¹¹, OCONH-T¹¹, O—CO-T¹¹, O—CO—O-T¹¹, OCO-alkyl-NH-T¹¹,OCO-alkyl-N(T¹¹)₂, O-alkyl-OCO-T¹¹, or O-T¹¹. In some embodiments, R² isH, OH, SH, CF₃, COOH, alkyl-OH, halogen, OCONH-alkyl-T¹¹, or—O-COalkyl-T¹¹. In some embodiments, R² is H, OH, CF₃, COOH,OCONH-alkyl-T¹¹, or —O-COalkyl-T¹¹. In some embodiments, R² is H. Insome embodiments, R² is OH. In some embodiments, R² is CF₃. In someembodiments, R² is COOH. In some embodiments, R² is OCONH-alkyl-T¹¹. Insome embodiments, R² is —O-COalkyl-T¹¹.

In some embodiments, T¹¹ is H, alkyl, halogen, OH, CF₃, CF₂H, COOH,COOalkyl, ONO₂, aromatic ring, heteroaromatic ring, a heterocyclic ring,or NQ¹¹Q¹², or T¹¹ is an ammonium group, wherein said ammonium group canbe independently substituted one or more times with a C1 to C6 alkylradical, or is a C3 to C7 heterocycle containing a nitrogen heteroatomfor bond formation. In some embodiments, T¹¹ is H, alkyl, halogen, OH,CF₃, CF₂H, COOH, COOalkyl, ONO₂, aromatic ring, heteroaromatic ring, aheterocyclic ring, or NQ¹¹Q¹², or T¹ is an ammonium group, wherein saidammonium group can be independently substituted one or more times with aC1 to C6 alkyl radical. In some embodiments, T¹¹ is H, alkyl, halogen,OH, CF₃, CF₂H, COOH, COOalkyl, ONO₂, aromatic ring, heteroaromatic ring,a heterocyclic ring, or NQ¹¹Q¹². In some embodiments, T¹¹ is H, alkyl,halogen, OH, CF₃, CF₂H, COOH, COOalkyl, ONO₂, or NQ¹¹Q¹². In someembodiments, T¹¹ is H, alkyl, halogen, OH, CF₃, CF₂H, COOH, COOalkyl, orONO₂. In some embodiments, T¹¹ is H, alkyl, halogen, CF₃, CF₂H, COOH orCOOalkyl. In some embodiments, is H, alkyl, halogen, CF₃, or CF₂H. Insome embodiments, T¹¹ is H, alkyl, or CF₃. In some embodiments, is H oralkyl. In some embodiments, T¹¹ is H or methyl. In some embodiments, T¹¹is H. In some embodiments, T¹¹ is methyl.

In some embodiments, s is 0 to 10. In some embodiments, s is 0 to 6. Insome embodiments, s is 0 to 4. In some embodiments, s is 0 to 2. In someembodiments, s is 0 or 1. In some embodiments, s is 0. In someembodiments, s is 1.

In some embodiments, X¹¹ and Y¹¹ are H, alkyl-OCO-alkyl, oralkyl-O—CO—O-alkyl. In some embodiments, X¹¹ and Y¹¹ are H oralkyl-OCO-alkyl. In some embodiments, X¹¹ is H, alkyl-OCO-alkyl,alkyl-O—CO—O-alkyl, alkali metal or alkaline earth metal. In someembodiments, X¹¹ is H, alkyl-OCO-alkyl, or alkyl-O—CO—O-alkyl. In someembodiments, X¹¹ is H. In some embodiments, is H, alkyl-OCO-alkyl,alkyl-O—CO—O-alkyl, alkali metal or alkaline earth metal. In someembodiments, Y¹¹ is H, alkyl-OCO-alkyl or alkyl-O—CO—O-alkyl. In someembodiments, Y¹¹ is H.

In some embodiments, Q¹¹ and Q¹² are each independently H or alkyl, orQ¹¹ and Q¹² together are part of a heterocyclic ring having about 4 toabout 7 ring members and optionally one additional heteroatom selectedfrom O, N or S. In some embodiments, Q¹¹ and Q¹² are each independentlyH or alkyl. In some embodiments, Q¹¹ and Q¹² are each independently H ormethyl. In some embodiments, Q¹¹ and Q¹² are each H. In someembodiments, Q¹¹ and Q¹² are each methyl.

In some embodiments, Q¹³ is H, alkyl, or alkyl-NQ¹¹Q¹². In someembodiments, Q¹³ is H or alkyl. In some embodiments, Q¹³ is H or methyl.In some embodiments, Q¹³ is H. In some embodiments, Q¹³ is H or alkyl.In some embodiments, Q¹³ is methyl.

In some embodiments, D¹ is an optionally substituted alkyl group,alkenyl group, alkenylene, alkynyl group, cycloalkyl, a carbocyclicgroup, a spirocyclic ring, a polycyclic ring, a heterocyclic ring, anaromatic ring, a heteroaromatic ring, C═O(O), 0(C═O), CONH, NHCO, O, S,SO₂, SO₂NH, NHSO₂, NH(alkyl), NH, or OSO₂. In some embodiments, D¹ is aalkyl group, alkenyl group, alkenylene, alkynyl group, cycloalkyl, acarbocyclic group, a heterocyclic ring, an aromatic ring, aheteroaromatic ring, C═O(O), 0(C═O), CONH, NHCO, O, S, SO₂, SO₂NH,NHSO₂, NH(alkyl), NH, or OSO₂. In some embodiments, D¹ is a alkyl group,alkenyl group, alkenylene, alkynyl group, cycloalkyl, a carbocyclicgroup, an aromatic ring, C═O(O), O(C═O), CONH, NHCO, O, S, SO₂, SO₂NH,NHSO₂, NH(alkyl), NH, or OSO₂. In some embodiments, D¹ is a alkyl group,alkenyl group, alkenylene, alkynyl group, cycloalkyl, C═O(O), O(C═O),CONH, NHCO, O, S, SO₂, SO₂NH, NHSO₂, NH(alkyl), NH, or OSO₂. In someembodiments, D¹ is a alkyl group, alkenyl group, alkenylene, alkynylgroup or cycloalkyl. In some embodiments, D¹ is a alkyl group. In someembodiments, D¹ is a —(C1-C6)-alkyl group. In some embodiments, D¹ is a—(C1-C3)-alkyl group. In some embodiments, D¹ is a methyl group.

In some embodiments, J¹ and J² are each independently selected fromalkyl, O, NH, N, COO, OCO, O—CO—O, CONH, NHCO, OSO₂, SO₂NH, and NHSO₂.In some embodiments, J¹ and J² are each independently selected fromalkyl. In some embodiments, J¹ and J² are each present. In someembodiments, J¹ is present. In some embodiments, J¹ and J² are absent.

In some embodiments, C is an optionally substituted cyclohexyl ring,bicyclic ring, aromatic ring, heterocyclic ring, heteroaromatic ring, orterpene. In some embodiments, C is an optionally substituted cyclohexylring, cyclodecyl ring, phenyl ring, naphthyl ring, piperazine ring,heteroaromatic ring or terpene. In some embodiments, C is an optionallysubstituted cyclohexyl ring, phenyl ring, naphthyl ring, piperazinering, or terpene. In some embodiments, C is a cyclohexyl ring. In someembodiments, C is a phenyl ring. In some embodiments, C is a terpene.

In some embodiments, A is an optionally substituted aromatic ring,heteroaromatic ring, or heterocyclic ring. In some embodiments, A is anoptionally substituted phenyl ring, naphthyl ring, indole ring, orhydroxypyridine ring. In some embodiments, A is a phenyl ring ornaphthyl ring. In some embodiments, A is a phenyl ring.

In some embodiments, G is a direct bond or a group selected from C═O,NH, CH₂, CONH, NHCO, S, SO, SO₂, and O. In some embodiments, G is notpresent. In some embodiments, G is a direct bond or a group selectedfrom C═O, NH, CH₂, and O. In some embodiments, G is a direct bond or agroup selected from C═O, NH, and O. In some embodiments, G is a directbond or a group selected from C═O, NH, and O. In some embodiments, G isa direct bond. In some embodiments, G is C═O. In some embodiments, G isNH. In some embodiments, G is CH₂. In some embodiments, G is O.

In some embodiments, M is CH₂. In some embodiments, M is alkyl-V. Insome embodiments, M is alkyl.

In some embodiments, L is alkyl. In some embodiments, L is alkyl-V. Insome embodiments, L is CH₃.

In some embodiments, P is H or alkyl-ONO₂. In some embodiments, P is H.

In some embodiments, P is alkyl-ONO₂.

In some embodiments, the compounds of Formula (I)-(IX) includes:2-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)ethylnitrate; 3-((6 aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)propylnitrate; 4-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)butyl nitrate;4-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)pentylnitrate;6-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)hexylnitrate; 7-((6aR,10aR)-1-hydroxy-6, 6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)heptylnitrate; 8-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)octylnitrate;9-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)nonylnitrate;2-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-2-methylpropylnitrate;3-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate;4-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate;5-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate;6-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-6-methylheptylnitrate; 7-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyloctyl nitrate;8-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-8-methylnonylnitrate; (6aR,10aR)-6, 6,9-trimethyl-3-(nitrooxy)pentyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl 2-propylpentanoate;(6aR,10aR)-6,6,9-trimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl2-propylpentanoate;(6aR,10aR)-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-6,6,9-trimethyl-3-propyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;2-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)ethylnitrate;3-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrabydro-6H-benzo[c]chromen-3-yl)propylnitrate; 4-((6aR,10aR)-1-hydroxy-6, 6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)butyl nitrate;5-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)pentylnitrate;6-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)hexylnitrate;7-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)heptylnitrate;8-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)octylnitrate; 9-((6aR,10aR)-1-hydroxy-6, 6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)nonyl nitrate;2-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-2-methylpropylnitrate;3-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate;4-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate;5-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate;6-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-6-methylheptylnitrate;7-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;8-46aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-8-methylnonylnitrate;(6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl2-propylpentanoate;(6aR,10aR)-6,6,9-trimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl2-propylpentanoate;(6aR,10aR)-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butan oate;(6aR,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(E)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid;(E)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid;(E)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(3-(nitrooxy)propyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid;(E)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(3-(nitrooxy)propyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid;(Z)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid; (Z)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid;(Z)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(3-(nitrooxy)propyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid;(Z)-4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(3-(nitrooxy)propyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)but-2-enoicacid;(6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(6aR,10aR)-6,6,9-trimethyl-3-(2-(nitrooxy)ethyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)butanoicacid;4-oxo-4-(((6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)butanoicacid;(6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-methylbenzenesulfonate; (6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ylbenzylcarbamate;(6aR,10aR)-3-(adamantan-1-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;7-((6aR,10aR)-1-methoxy-6,6-dimethyl-9-methylene-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;(6aR,10aR)-6,6-dimethyl-9-methylene-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ylnitrate;7-(1-hydroxy-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yl)-6-methyloctylnitrate;6,6,9-trimethyl-3-(3-methyloctan-2-yl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; 2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyloct-7-yn-2-yl)phenyl4-(nitrooxy)butanoate;8-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)nonylnitrate;5-((6aS,10aR)-1-hydroxy-9-methyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)pentylnitrate;5-((6aS,10aS)-1-hydroxy-9-methyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)pentylnitrate;6-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)heptylnitrate;N,N,N-trimethyl-2-oxo-2-(((6aR,10aR)-6,6,9-trimethyl-3-(5-(nitrooxy)pentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)ethanaminiumiodide; 3-(((6aR,10aR)-3-((1s,3S)-adamantan-1-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)propylnitrate;7-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)hept-5-en-1-ylnitrate;7-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)hept-5-yn-1-ylnitrate;5-((6aR,10aR)-6,6-difluoro-1-hydroxy-9-methyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)pentylnitrate;(6aR,10aR)-6,6-difluoro-9-methyl-3-(2-methyl-6-(nitrooxy)hexan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl2-propylpentanoate;7-((6aR,10aR)-6,6-difluoro-1-hydroxy-9-methyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyl-6-oxooctylnitrate;(E)-4-(((6aR,10aR)-6,6-difluoro-9-methyl-3-(2-methyl-8-(nitrooxy)-3-oxooctan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(6aR,10aR)-6,6-difluoro-9-methyl-3-(2-methyl-3-oxooctan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;3-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl)-3-methylbutyl nitrate;4-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl)-4-methylpentyl nitrate;5-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl)-5-methylhexyl nitrate;6-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl)-6-methylheptyl nitrate;7-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl)-7-methyloctyl nitrate;1-hydroxy-3-(2-methyloctan-2-yl)-6-oxo-6H-benzo[c]chromen-9-yl nitrate;6-((l-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)(methyl)amino)hexylnitrate;3-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate;4-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate;5-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate;6-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-6-methylheptylnitrate;7-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;9-methoxy-3-(2-methyl-8-(nitrooxy)octan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl2-propylpentanoate; 9-methoxy-3-(2-methyloctan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl 4-(nitrooxy)butanoate;(E)-4-((9-methoxy-3-(2-methyloctan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(Z)-4-((9-methoxy-3-(2-methyloctan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;9-methoxy-3-(2-methyl-8-(nitrooxy)octan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;4-((9-methoxy-3-(2-methyloctan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl)oxy)-4-oxobutanoicacid;3-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate;4-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate;5-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate;6-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)-6-methylheptylnitrate;7-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;9-methoxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6H-benzo[c]chromen-1-yl4-(nitro oxy)butanoate; (3-((1s,3s)-adamantan-1-yl)-1-hydroxy-6,6-dimethyl-6H-benzo[c]chromen-9-yl)methylnitrate;3-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate;4-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate;5-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate;6-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-6-methylheptylnitrate;7-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;((6aR,9R,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-yl)methylnitrate; 4-(nitrooxy)butyl2-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-2-methylpropanoate;((6R,6aR,9R,10aR)-3-((1s,3S)-adamantan-1-yl)-6-ethynyl-1-hydroxy-6-methyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-yl)methylnitrate;((6aR,9R,10aR)-3-((1s,3S)-adamantan-1-yl)-1-hydroxy-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-yl)methylnitrate;(6R,6aR,9R,10aR)-3-((1s,3S)-adamantan-1-yl)-6,9-bis(hydroxymethyl)-6-methyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; (6R,6aR,9R,10aR)-6,9-bis(hydroxymethyl)-6-methyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; 4-(nitrooxy)butyl2,2-difluoro-2-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)acetate;(6aR,9R,10aR)-1-hydroxy-6,6-dimethyl-3-(tert-pentyl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-ylnitrate;(6aR,9R,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methylpentan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-ylnitrate;(6aR,9R,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methylhexan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-ylnitrate; (6aR,9R,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methylheptan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-ylnitrate;(6aR,9R,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-9-ylnitrate;3-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate;4-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate;5-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate;6-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-6-methylheptylnitrate;7-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;1-(((((6aR,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)carbonyl)oxy)ethylisobutyrate;7-((6aS,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;(6aR,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl2-propylpentanoate;(6aS,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl2-propylpentanoate; (E)-4-(((6aR,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(E)-4-(((6aS,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(Z)-4-(((6aR,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(Z)-4-(((6aS,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(6aR,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;4-(((6aR,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobutanoicacid;7,7-difluoro-7-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)heptylnitrate;7,7-difluoro-7-((6aS,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)heptylnitrate; 4-(nitrooxy)butyl2-((6aS,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-2-methylpropanoate;4-(nitrooxy)butyl 2,2-difluoro-2-((6aS,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)acetate;4-(nitrooxy)butyl2,2-difluoro-2-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)acetate;4-(nitrooxy)butyl2-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-2-methylpropanoate; 4-(nitrooxy)butyl2-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)propanoate;(E)-4-(((6aR,10aR)-3-(1,1-difluoro-7-(nitrooxy)heptyl)-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(Z)-4-(((6aR,10aR)-3-(1,1-difluoro-7-(nitrooxy)heptyl)-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(6S,6aR,9R,10aR)-9-hydroxy-6-methyl-3-(((R)-5-phenylpentan-2-yl)oxy)-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-1-yl4-(nitrooxy)butanoate; 3-((6aR,9R,10aR)-1,9-dihydroxy-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate; 4-((6aR,9R,10 aR)-1,9-dihydroxy-6,6-dimethyl-6a,7,8,9, 10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-4-methylpentyl nitrate;5-((6aR,9R,10aR)-1,9-dihydroxy-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate; 6-((6aR,9R,10aR)-1,9-dihydroxy-6,6-dimethyl-6a,7, 8,9, 10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-6-methylheptyl nitrate;7-((6aR,9R,10aR)-1,9-dihydroxy-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate; 7-((6aR,9S,10aR)-1,9-dihydroxy-6,6-dimethyl-6a,7,8,9, 10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctyl nitrate;7-((6aR,10aR)-9-((1H-imidazol-1-yl)methyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate; 3-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-3-methylbutyl nitrate;4-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate; 5-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-5-methylhexyl nitrate;6-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-6-methylheptylnitrate;7-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;((6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methylnonan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl)methylnitrate;7-((6aS,10aS)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate;3-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-3-methylbutylnitrate;4-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-4-methylpentylnitrate;5-((6aS,10aS)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate; 6-((6aS,10aS)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-6-methylheptyl nitrate;7-((6aR,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate; 2-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9, 10,10a-octahydrophenanthridin-3-yl)oxy)ethyl nitrate; 3-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-3-yl)oxy)propylnitrate;4-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-3-yl)oxy)butylnitrate;5-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-3-yl)oxy)pentylnitrate;6-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-3-yl)oxy)hexylnitrate; 2-(nitrooxy)ethyl2-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-2-methylpropanoate;3-(nitrooxy)propyl2-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-2-methylpropanoate;4-(nitrooxy)butyl2-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-2-methylpropanoate;5-(nitrooxy)pentyl2-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-2-methylpropanoate;(E)-4-((9-methoxy-3-(2-methyl-1-((5-(nitrooxy)pentyl)oxy)-1-oxopropan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;(Z)-4-((9-methoxy-3-(2-methyl-1-((5-(nitrooxy)pentyl)oxy)-1-oxopropan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl)oxy)-4-oxobut-2-enoicacid;9-methoxy-3-(2-methyl-1-((5-(nitrooxy)pentyl)oxy)-1-oxopropan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;4-((9-methoxy-3-(2-methyl-1-((5-(nitrooxy)pentyl)oxy)-1-oxopropan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl)oxy)-4-oxobutanoicacid;9-methoxy-3-(2-methyl-1-((5-(nitrooxy)pentyl)oxy)-1-oxopropan-2-yl)-6-oxo-6H-benzo[c]chromen-1-yl2-propylpentanoate;3-(1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)-9-methoxy-6-oxo-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; 2-(nitrooxy)ethyl2,2-difluoro-2-(1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)acetate;3-(nitrooxy)propyl2,2-difluoro-2-(1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)acetate;4-(nitrooxy)butyl2,2-difluoro-2-(1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)acetate;5-(nitrooxy)pentyl2,2-difluoro-2-(1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)acetate;3-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl2-propylpentanoate;3-(1,1-difluoro-2-oxo-2-(pentyloxy)ethyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-3-(1,1-difluoropropyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-3-(1,1-difluorobutyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-3-(1,1-difluoropentyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-3-(1,1-difluorohexyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-3-(1,1-difluoroheptyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; (6aR,10aR)-3-(1,1-difluoropropyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; (6aR,10aR)-3-(1,1-difluorobutyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; (6aR,10aR)-3-(1, 1-difluoropentyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; (6aR,10aR)-3-(1,1-difluorohexyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate; (6aR,10aR)-3-(1, 1-difluoroheptyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl4-(nitrooxy)butanoate;(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-4-(nitrooxy)butan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid;(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-5-(nitrooxy)pentan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid;(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-6-(nitrooxy)hexan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid; (6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-7-(nitrooxy)heptan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid;(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid;(6aR,10aR)-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-1-((2-propylpentanoyl)oxy)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid; sodium(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylate;(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(3-(nitrooxy)propyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid;(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(4-(nitrooxy)butyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid; (6aS,10aS)-1-hydroxy-6,6-dimethyl-3-(5-(nitrooxy)pentyl)-6a, 7,8,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid;(6aS,10aS)-1-hydroxy-6,6-dimethyl-3-(6-(nitrooxy)hexyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid;(6aR,10aR)-1-hydroxy-6, 6-dimethyl-3-(7-(nitrooxy)heptyl)-6a, 7,8,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylic acid; sodium(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(7-(nitrooxy)heptyl)-6a,7,8,10a-tetrabydro-6H-benzo[c]chromene-9-carboxylate;((1R,3R,4R)-3-(4-((1s,3S)-adamantan-1-yl)-2,6-dihydroxyphenyl)-4-(prop-1-en-2-yl)cyclohexyl)methylnitrate;5,5-dimethyl-8-(3-methyl-8-(nitrooxy)octan-2-yl)-2-(prop-2-yn-1-yl)-2,3,4,5-tetrahydro-1H-chromeno[4,3-c]pyridin-10-yl4-(piperidin-1-yl)butanoate;6-(5-hydroxy-2,2-dimethyl-4-(pyridin-4-yl)-2H-chromen-7-yl)-5-methylheptylnitrate;7-(5-hydroxy-2,2-dimethyl-4-(pyridin-4-yl)-2H-chromen-7-yl)-6-methyloctylnitrate;6-(5-hydroxy-2-oxo-4-(pyridin-4-yl)-2H-chromen-7-yl)-5-methylheptylnitrate;7-(5-hydroxy-2-oxo-4-(pyridin-4-yl)-2H-chromen-7-yl)-6-methyloctylnitrate;7-(5-hydroxy-2-oxo-4-(pyridin-4-ylmethyl)-2H-chromen-7-yl)-7-methyloctylnitrate;6-(5-methoxy-2-oxo-4-(pyridin-4-ylmethyl)-2H-chromen-7-yl)-6-methylheptylnitrate;3-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-3-methylbutylnitrate;4-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-4-methylpentylnitrate;5-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-5-methylhexylnitrate;6-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-6-methylheptylnitrate;7-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate;3-((1′R,2R′)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)propylnitrate;4-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)butylnitrate;5-((1′R,2′R)-2,6-dihydroxy-5′-(hydroxymethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)pentylnitrate;6-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)hexylnitrate;7-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)heptylnitrate;3-((1′S,2′S)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)propylnitrate;4-((1′S,2′S)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-4-methylpentylnitrate;5-((1′S,2′S)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-5-methylhexylnitrate;6-((1′S,2′S)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-6-methylheptylnitrate;7-((1′S,2′S)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate;((1S,6S)-2′,6′-dihydroxy-4′-(2-methyl-4-(nitrooxy)butan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylacetate;((1S,6S)-2′,6′-dihydroxy-4′-(2-methyl-5-(nitrooxy)pentan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylacetate;((1S,6S)-2′,6′-dihydroxy-4′-(2-methyl-6-(nitrooxy)hexan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylacetate;((1S,6S)-2′,6′-dihydroxy-4′-(2-methyl-7-(nitrooxy)heptan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylacetate;41S,6S)-2′,6′-dihydroxy-4′-(2-methyl-8-(nitrooxy)octan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylacetate;3-((1′S,2′S)-2,6-dihydroxy-5′-(hydroxymethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)propylnitrate;4-((1′S,2′S)-2,6-dihydroxy-5′-(hydroxymethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)butylnitrate;5-((1′S,2′S)-2,6-dihydroxy-5′-(hydroxymethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-5-methylhexylnitrate;6-((1′S,2′S)-2,6-dihydroxy-5′-(hydroxymethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)hexylnitrate;7-((1′S,2′S)-2,6-dihydroxy-5′-(hydroxymethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate;(1S,6S)-2′,6′-dihydroxy-4′-(3-(nitrooxy)propyl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-carboxylicacid;(1S,6S)-2′,6′-dihydroxy-4′-(4-(nitrooxy)butyl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-carboxylicacid;(1S,6S)-2′,6′-dihydroxy-4′-(2-methyl-6-(nitrooxy)hexan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-carboxylicacid;(1S,6S)-2′,6′-dihydroxy-4′-(6-(nitrooxy)hexyl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-carboxylicacid;(1S,6S)-2′,6′-dihydroxy-4′-(2-methyl-8-(nitrooxy)octan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-carboxylicacid;(E)-4-(((1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-8-(nitrooxy)octan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-4-oxobut-2-enoicacid;(Z)-4-(((1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-8-(nitrooxy)octan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-4-oxobut-2-enoicacid;1-(((((1′S,2′S)-6-hydroxy-5′-methyl-4-(2-methyl-6-(nitrooxy)hexan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)carbonyl)oxy)ethylisobutyrate;4-(((1′R,2′R)-6-hydroxy-5′-methyl-4-(7-(nitrooxy)heptyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-4-oxobutanoicacid;(1′S,2′S)-6-hydroxy-5′-methyl-4-(2-methyl-8-(nitrooxy)octan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl2-propylpentanoate; sodium(1S,6S)-2′,6′-dihydroxy-4′-(2-methyl-8-(nitrooxy)octan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-carboxylate;(1′S,2′S)-6-hydroxy-5′-methyl-4-(2-methyl-6-(nitrooxy)hexan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(1′S,2′S)-5′-(acetoxymethyl)-6-hydroxy-4-(2-methyloctan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;7-((1′S,2′S)-2,6-dimethoxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate;2-(((1′S,2′S)-6-hydroxy-5′-methyl-4-(2-methyl-6-(nitrooxy)hexan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-N,N,N-trimethyl-2-oxoethanaminiumiodide;(2E,2′E)-4,4′-(((1′R,2′R)-5′-methyl-4-(2-methyl-8-(nitrooxy)octan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diyl)bis(oxy))bis(4-oxobut-2-enoicacid);3-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-3-methylbutylnitrate;4-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-4-methylpentylnitrate;5-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-5-methylhexylnitrate;6-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-6-methylheptylnitrate;7-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-7-methyloctylnitrate;3-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-3-methylbutylnitrate;4-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-4-methylpentylnitrate;5-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-5-methylhexylnitrate; 6-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-6-methylheptylnitrate;7-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-7-methyloctylnitrate;(E)-4-(2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-7-(nitrooxy)heptan-2-yl)phenoxy)-4-oxobut-2-enoicacid;(E)-4-(2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-4-oxobut-2-enoicacid;(Z)-4-(2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-4-oxobut-2-enoic acid;4-(2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-4-oxobutanoicacid;4,4′-((2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-5-(2-methyl-8-(nitrooxy)octan-2-yl)-1,3-phenylene)bis(oxy))bis(4-oxobutanoicacid);2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenyl 2,5,8,11,14,17,20-heptaoxadocosan-22-oate;2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenyl 2-propylpentanoate;1-(((2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)carbonyl)oxy)ethylisobutyrate;2-((1R,2S,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyloctan-2-yl)phenyl4-(nitrooxy)butanoate;2-(2-((1R,2S,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-N,N,N-trimethyl-2-oxoethanaminium iodide;(E)-4-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-6-(nitrooxy)hexan-2-yl)phenoxy)-4-oxobut-2-enoicacid;(E)-4-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-4-oxobut-2-enoicacid;(Z)-4-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-4-oxobut-2-enoic acid;4-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-4-oxobutanoicacid;4,4′-((2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-5-(2-methyl-8-(nitrooxy)octan-2-yl)-1,3-phenylene)bis(oxy))bis(4-oxobutanoicacid);2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenyl2,5,8,11,14,17,20-heptaoxadocosan-22-oatc;2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenyl2-propylpentanoate; 1-(((2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)carbonyl)oxy)ethylisobutyrate; 2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyloctan-2-yl)phenyl4-(nitrooxy)butanoate;2-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenoxy)-N,N,N-trimethyl-2-oxoethanaminiumiodide;5-benzoyl-2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenyl4-(nitrooxy)butanoate;((1R,3R,4R)-3-(4-((1s,3S)-adamantan-1-yl)-2,6-dihydroxyphenyl)-4-(prop-1-en-2-yl)cyclohexyl)methylnitrate;((1R,3R,4S)-3-(4-((1s,3S)-adamantan-1-yl)-2,6-dihydroxyphenyl)-4-isopropylcyclohexyl)methylnitrate;7-((1′R,6′R)-2-hydroxy-3′-methyl-3,6-dioxo-6′-(prop-1-en-2-yl)-[1,1′-bi(cyclohexane)]-1,2′,4-trien-4-yl)-7-methyloctylnitrate;5-((1′R,6′R)-2-hydroxy-3′-methyl-3,6-dioxo-6′-(prop-1-en-2-yl)-[1,1′-bi(cyclohexane)]-1,2′,4-trien-4-yl)pentylnitrate; 2-(nitrooxy)ethyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;3-(nitrooxy)propyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;4-(nitrooxy)butyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;5-(nitrooxy)pentyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;6-(nitrooxy)hexyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;2-(nitrooxy)ethyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;3-(nitrooxy)propyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;4-(nitrooxy)butyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;5-(nitrooxy)pentyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;6-(nitrooxy)hexyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;(E)-4-(((1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-4-oxobut-2-enoicacid;(1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;(1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(1′S,2′S)-5′-(acetoxymethyl)-6-hydroxy-4-(2-methyl-1-oxo-1-propoxypropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;(1′S,2′S)-5′-(acetoxymethyl)-6-hydroxy-4-(2-methyl-1-(3-(nitrooxy)propoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl2-propylpentanoate;4,4′-(((1′S,2′S)-5′-(acetoxymethyl)-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diyl)bis(oxy))bis(4-oxobutanoicacid);(1′S,2′S)-5′-(acetoxymethyl)-4-(1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)-6-hydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;2-(((1′S,2′S)-5′-(acetoxymethyl)-6-hydroxy-4-(2-methyl-1-((6-(nitrooxy)hexyl)oxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-N,N,N-trimethyl-2-oxoethanaminiumiodide; 2-(nitrooxy)ethyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;3-(nitrooxy)propyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;4-(nitrooxy)butyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;5-(nitrooxy)pentyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-cn-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;6-(nitrooxy)hexyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;2-(nitrooxy)ethyl 2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;3-(nitrooxy)propyl 2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate; 4-(nitrooxy)butyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;5-(nitrooxy)pentyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;6-(nitrooxy)hexyl2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;(1′R,2′R)-4-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-6-hydroxy-5′-methyl-T-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;(1′R,2′R)-4-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-6-hydroxy-5′-methyl-T-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(E)-4-(((1′R,2′R)-4-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-6-hydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-4-oxobut-2-enoicacid;(1′S,2′S)-5′-(acetoxymethyl)-4-(1,1-difluoro-2-oxo-2-propoxyethyl)-6-hydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;(1′S,2′S)-5′-(acetoxymethyl)-4-(1,1-difluoro-2-(3-(nitrooxy)propoxy)-2-oxoethyl)-6-hydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl2-propylpentanoate;4,4′-(((1′S,2′S)-5′-(acetoxymethyl)-4-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diyl)bis(oxy))bis(4-oxobutanoicacid);(1′S,2′S)-5′-(acetoxymethyl)-4-(1,1-difluoro-2-(hexyloxy)-2-oxoethyl)-6-hydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;2-(((1′S,2′S)-5′-(acetoxymethyl)-4-(1,1-difluoro-2-((6-(nitrooxy)hexyl)oxy)-2-oxoethyl)-6-hydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-N,N,N-trimethyl-2-oxoethanaminiumiodide; 2-(nitrooxy)ethyl 2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;3-(nitrooxy)propyl 2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;4-(nitrooxy)butyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;5-(nitrooxy)pentyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;6-(nitrooxy)hexyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;2-(nitrooxy)ethyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;3-(nitrooxy)propyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;4-(nitrooxy)butyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;5-(nitrooxy)pentyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;6-(nitrooxy)hexyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2-methylpropanoate;(E)-4-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)phenoxy)-4-oxobut-2-enoicacid;2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-1-(3-(nitrooxy)propoxy)-1-oxopropan-2-yl)phenyl2-propylpentanoate; 4,4′-((2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-5-(2-fluoro-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-1,3-phenylene)bis(oxy))bis(4-oxobutanoicacid);2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-5-(1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)-3-hydroxyphenyl4-(nitrooxy)butanoate;2-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-1-((6-(nitrooxy)hexyl)oxy)-1-oxopropan-2-yl)phenoxy)-N,N,N-trimethyl-2-oxoethanaminiumiodide;2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)phenyl4-(nitrooxy)butanoate;2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)phenyl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(E)-4-(2-41R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)phenoxy)-4-oxobut-2-enoicacid; 2-(nitrooxy)ethyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(((1-(isobutyryloxy)ethoxy)carbonyl)oxy)phenyl)-2-methylpropanoate;2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyl-8-(nitrooxy)octan-2-yl)phenyl2-propylpentanoate; 3-(nitrooxy)propyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;4-(nitrooxy)butyl 2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;5-(nitrooxy)pentyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;6-(nitrooxy)hexyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;2-(nitrooxy)ethyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;3-(nitrooxy)propyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;4-(nitrooxy)butyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;5-(nitrooxy)pentyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;6-(nitrooxy)hexyl2-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-2,2-difluoroacetate;(E)-4-(5-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenoxy)-4-oxobut-2-enoicacid; 5-(1,1-difluoro-2-(3-(nitrooxy)propoxy)-2-oxoethyl)-2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenyl2-propylpentanoate;4,4′-((5-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-1,3-phenylene)bis(oxy))bis(4-oxobutanoicacid);5-(1,1-difluoro-2-(hexyloxy)-2-oxoethyl)-2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenyl4-(nitrooxy)butanoate;2-(5-(1,1-difluoro-2-((6-(nitrooxy)hexyl)oxy)-2-oxoethyl)-2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenoxy)-N,N,N-trimethyl-2-oxoethanaminium iodide;5-(1,1-difluoro-2-oxo-2-(pentyloxy)ethyl)-2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenyl4-(nitrooxy)butanoate;5-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenyl2,5,8,11,14,17,20-heptaoxadocosan-22-oate;(E)-4-(5-(1,1-difluoro-2-(4-(nitrooxy)butoxy)-2-oxoethyl)-2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenoxy)-4-oxobut-2-enoicacid;1-(((5-(1,1-difluoro-2-(2-(nitrooxy)ethoxy)-2-oxoethyl)-2-41R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxyphenoxy)carbonyl)oxy)ethylisobutyrate;((1S,6S)-2′,6′-dihydroxy-4′-(2-methyloctan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylnitrate;((1R,6R)-2′,6′-dihydroxy-4′-(2-methyloctan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrabydro-[1,1′-biphenyl]-3-yl)methylnitrate;((1S,6S)-2′,6′-dihydroxy-4′-pentyl-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylnitrate;((1R,6R)-2′,6′-dihydroxy-4′-pentyl-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylnitrate;6-(2,6-dihydroxy-5′-methoxy-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)-6-methylheptylnitrate;7-(2,6-dihydroxy-5′-methoxy-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate;7-(2,6-dihydroxy-5′-methoxy-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)-7,7-difluoroheptylnitrate; 2-(nitrooxy)ethyl2-(2,6-dihydroxy-5′-methoxy-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;(S)-6-hydroxy-5′-methoxy-4-pentyl-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-2-yl4-(nitrooxy)butanoate;4,4-difluoro-4-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)butylnitrate; 4-(nitrooxy)butyl2-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)-2-methylpropanoate;4-(nitrooxy)butyl2,2-difluoro-2-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)acetate;7-(4-((1S,2S,5S)-4-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-yl)-3,5-dimethoxyphenyl)-7-methyl octyl nitrate;5-(4-((1S,2S,5S)-4-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-yl)-3,5-dimethoxyphenyl)pentylnitrate; 4-(nitrooxy)butyl 2-(4-((1S,2S,5S)-4-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-yl)-3,5-dimethoxyphenyl)-2-methylpropanoate;((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methylnonan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methylnitrate; 7,7-difluoro-7-(4-((1S,2S,5S)-4-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-yl)-3,5-dimethoxyphenyl)heptylnitrate; pentyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-((nitrooxy)methyl)bicyclo[3.1.1]hept-3-en-2-yl)-3,5-dimethoxyphenyl)-2-methylpropanoate;((1S,4S,5S)-4-(4-(1,1-difluorooctyl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methylnitrate; pentyl2-(4-((1S,2S,5S)-6,6-dimethyl-4-((nitrooxy)methyl)bicyclo[3.1.1]hept-3-en-2-yl)-3,5-dimethoxyphenyl)-2,2-difluoroacetate;7-(2,6-dihydroxy-3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate;5-(2,6-dihydroxy-3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-5-methylhexylnitrate; 7-(2-hydroxy-3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate; 2′-cyano-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl3-(nitrooxy)propane-1-sulfonate;2′-cyano-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl5-(nitrooxy)pentane-1-sulfonate;3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl3-(nitrooxy)propane-1-sulfonate;4-hydroxy-3-((2R)-2-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)phenyl3-(nitrooxy)propane-1-sulfonate;4-hydroxy-3-((2S)-2-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)phenyl3-(nitrooxy)propane-1-sulfonate; 4-(nitrooxy)butyl2-(2,6-dihydroxy-3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-2-methylpropanoate;4-(nitrooxy)butyl2-(2,6-dihydroxy-3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate;5-(3-hydroxy-4-((1S,3R)-3-hydroxycyclohexyl)phenyl)-5-methylhexylnitrate;7-(3-hydroxy-4-((1S,3R)-3-hydroxycyclohexyl)phenyl)-7-methyloctylnitrate;5-(3-hydroxy-4-((1S,3S)-3-hydroxycyclohexyl)phenyl)-5-methylhexylnitrate;7-(3-hydroxy-4-((1S,3S)-3-hydroxycyclohexyl)phenyl)-7-methyloctylnitrate; 4-(nitrooxy)butyl2-(3-hydroxy-4-((1S,3R)-3-hydroxycyclohexyl)phenyl)-2-methylpropanoate;4-(nitrooxy)butyl2-(3-hydroxy-4-((1S,3S)-3-hydroxycyclohexyl)phenyl)-2-methylpropanoate;8-(3-hydroxy-4-((1S,3R)-3-hydroxycyclohexyl)phenyl)-8-methylnonylnitrate; 4-(nitrooxy)butyl2,2-difluoro-2-(3-hydroxy-4-((1S,3S)-3-hydroxycyclohexyl)phenyl)acetate;4-(nitrooxy)butyl2,2-difluoro-2-(3-hydroxy-4-((1S,3R)-3-hydroxycyclohexyl)phenyl)acetate;8-(3-hydroxy-4-((1S,3S)-3-hydroxycyclohexyl)phenyl)-8-methylnonylnitrate;7-(3-hydroxy-4-((1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenyl)-7-methyloctylnitrate;7-(3-hydroxy-4-((1R,3R,4aS,7S,8aR)-3-hydroxy-7-(hydroxymethyl)decahydronaphthalen-1-yl)phenyl)-7-methyloctylnitrate;2-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)ethylnitrate;3-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)propylnitrate;3-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)propylnitrate;5-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)pentylnitrate;7-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-7-methyloctylnitrate;2-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)ethylnitrate;3-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)propylnitrate;3-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)propylnitrate;5-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)pentylnitrate;7-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-7-methyloctylnitrate;7-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-7,7-difluoroheptylnitrate;7-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-7,7-difluoroheptylnitrate; 4-(nitrooxy)butyl2-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-2-methylpropanoate;4-(nitrooxy)butyl2-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-2-methylpropanoate;4-(nitrooxy)butyl2-((1′R,2′R)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-2,2-difluoroacetate;4-(nitrooxy)butyl2-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)-2,2-difluoroacetate;3-(((1′R,2′R)-2-hydroxy-5′-methyl-6-(5-(nitrooxy)pentyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)-3-oxopropanoicacid;(E)-4-(((1′S,2′S)-2-hydroxy-5′-methyl-6-(5-(nitrooxy)pentyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)-4-oxobut-2-enoicacid;(Z)-4-(((1′S,2S)-2-hydroxy-5′-methyl-6-(5-(nitrooxy)pentyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)-4-oxobut-2-enoicacid;(1′R,2′R)-2-hydroxy-5′-methyl-6-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl4-(nitrooxy)butan oate; 3,5-dihydroxy-2-((1R,2S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenethyl nitrate;4-(3,5-dihydroxy-2-((1R,2S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenyl)butylnitrate;7-(3,5-dihydroxy-2-((1R,2S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenyl)-7-methyloctylnitrate;(E)-4-(3-hydroxy-5-(4-(nitrooxy)butyl)-4-((1R,2S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenoxy)-4-oxobut-2-enoicacid;3-hexyl-5-hydroxy-4-((1R,2S,5S)-4,6,6-trimethylbicyclo[3.1.1]kept-3-en-2-yl)phenyl4-(nitrooxy)butanoate; 4-(nitrooxy)butyl2-(3,5-dihydroxy-2-((1R,2S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenyl)-2-methylpropanoate;4-(nitrooxy)butyl 2-(3,5-dihydroxy-2-((1R,2S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenyl)-2,2-difluoroacetate;5-(3,5-dihydroxy-2-((1R,2R,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenyl)pentyl nitrate;5-(3,5-dihydroxy-2-((1R,2R,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-yl)phenyl)-5,5-difluoropentylnitrate;2-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)-3,5-dihydroxyphenethylnitrate;5-(3,5-dihydroxy-2-(1-isopropyl-4-methyl-1,2,5,6-tetrahydropyridin-2-yl)phenyl)pentylnitrate;3-hexyl-5-hydroxy-4-(1-isopropyl-4-methyl-1,2,5,6-tetrahydropyridin-2-yl)phenyl5-(nitrooxy)pentanoate; 4-(nitrooxy)butyl2-(3,5-dihydroxy-2-(1-isopropyl-4-methyl-1,2,5,6-tetrahydropyridin-2-yl)phenyl)-2-methylpropanoate;5-(2-cyclohexyl-3,5-dihydroxyphenyl)pentyl nitrate;4-cyclohexyl-3-hydroxy-5-pentylphenyl 5-(nitrooxy)pentanoate;7-(2-cyclohexyl-3,5-dihydroxyphenyl)-7-methyl-6-oxooctyl nitrate;5-(2-((1S,2S,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)pentylnitrate;5-(2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)pentylnitrate; 3-(nitrooxy)propyl1-(6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)cyclohexanecarboxylate;4-(nitrooxy)butyl1-(6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)cyclohexanecarboxylate;3-(nitrooxy)propyl1-(6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)cyclopentanecarboxylate;3-(nitrooxy)propyl2-(6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-methylpropanoate;3-(nitrooxy)propyl3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoate;((R)-1-((R)-5-(3,3-dimethylbutanamido)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydrobenzofuran-7-yl)ethoxy)methylnitrate;3-(((R)-7-((R)-1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)amino)-3-oxopropylnitrate;(R)-2-((1-(cyclohexylmethyl)-3-(3,4-dimethylpiperazine-1-carbonyl)-1H-indol-7-yl)oxy)ethylnitrate;(R)-3-(4-(1-(cyclohexylmethyl)-7-methoxy-1H-indole-3-carbonyl)-2-methylpiperazin-1-yl)propylnitrate;1-(cyclohexylmethyl)-3-((3S,5R)-3,4,5-trimethylpiperazine-1-carbonyl)-1H-indol-7-ylnitrate;(R)-5-(3-(3,4-dimethylpiperazine-1-carbonyl)-7-methoxy-1H-indol-1-yl)pentylnitrate; 5-(3-(1-naphthoyl)-1H-indol-1-yl)pentyl nitrate;4-((4-(1-naphthoyl)naphthalen-1-yl)oxy)butyl nitrate;5-(3-(2,2,3,3-tetramethylcyclopropanecarbonyl)-1H-indol-1-yl)pentylnitrate; 5-(3-((1-cyanocyclopropyl)carbamoyl)-1H-indol-1-yl)pentylnitrate; 4-(nitrooxy)butyl1-(3-chlorophenyl)-2,4-dioxopiperidine-3-carboxylate;4-*(2-(2,5-dichlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)oxy)butylnitrate;5-((2-(4-hydroxyphenethyl)-5-methoxy-1-oxoisoindolin-4-yl)amino)pentylnitrate;5-((3-((benzo[d][1,3]dioxol-5-ylmethyl)carbamoyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yl)oxy)pentylnitrate;3-(4-((2-((2,4-dichlorophenyl)amino)-4-(trifluoromethyl)pyrimidine-5-carboxamido)methyl)piperidin-1-yl)propylnitrate;3-(4-(2-(1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)ethyl)piperazin-1-yl)propylnitrate;2-((1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-morpholinoethyl)-1H-indol-5-yl)oxy)ethylnitrate;((1R,3r)-3-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)adamantan-1-yl)methylnitrate;((1R,3r)-3-(4-((1S,2R,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)adamantan-1-yl)methylnitrate;2-(((1R,3r)-3-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)adamantan-1-yl)methoxy)ethylnitrate;((1R,3r)-3-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)adamantan-1-yl)methylnitrate;((1R,3r)-3-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)adamantan-1-yl)methylnitrate;((1R,3r)-3-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)adamantan-1-yl)methylnitrate;((1S,3r)-3-((1′S,2′S)-2,6-dihydroxy-5′-(hydroxymethyl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)adamantan-1-yl)methylnitrate;2-((1R,3r)-3-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)adamantane-1-carboxamido)ethylnitrate;2-((1R,3r)-3-(4-((1S,2R,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)adamantane-1-carboxamido)ethylnitrate;2-(((1R,3r)-3-(4-((1S,2R,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)adamantan-1-yl)methoxy)ethylnitrate;3-(1-(3-(nitrooxy)propyl)-1H-indazole-3-carboxamido)adamantane-1-carboxylicacid; 3-(3-((1-cyanocyclopropyl)carbamoyl)-1H-indazol-1-yl)propylnitrate; 2-(3-(adamantan-1-ylcarbamoyl)-1H-indazol-1-yl)ethyl nitrate;or a pharmaceutically acceptable salt of any such compound.

In certain embodiments, a compound is provided, wherein the compound is:

In further aspects of the technology, a composition is providedcomprising any of the compounds described herein, and at least apharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients are non-toxic, aidadministration, and do not adversely affect the therapeutic benefit ofthe compound. Such excipients may be any solid, liquid, semi-solid or,in the case of an aerosol composition, gaseous excipient that isgenerally available to one of skill in the art. Pharmaceuticalcompositions in accordance with the technology are prepared byconventional means using methods known in the art.

The compositions disclosed herein may be used in conjunction with any ofthe vehicles and excipients commonly employed in pharmaceuticalpreparations, e.g., talc, gum arabic, lactose, starch, magnesiumstearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffinderivatives, glycols, etc. Coloring and flavoring agents may also beadded to preparations, particularly to those for oral administration.Solutions can be prepared using water or physiologically compatibleorganic solvents such as ethanol, 1,2-propylene glycol, polyglycols,dimethylsulfoxide, fatty alcohols, triglycerides, partial esters ofglycerin and the like.

Solid pharmaceutical excipients include starch, cellulose, hydroxypropylcellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, magnesium stearate, sodium stearate, glycerolmonostearate, sodium chloride, dried skim milk and the like. Liquid andsemisolid excipients may be selected from glycerol, propylene glycol,water, ethanol and various oils, including those of petroleum, animal,vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineraloil, sesame oil, etc. In certain embodiments, the compositions providedherein comprises one or more of α-tocopherol, gum arabic, and/orhydroxypropyl cellulose.

In some embodiments, the CNE compounds are formulated intopharmaceutical compositions for administration to subjects in abiologically compatible form suitable for administration in vivo.According to another aspect, the present technology provides apharmaceutical composition comprising a CNE compound described herein inadmixture with a pharmaceutically acceptable diluent and/or carrier. Thepharmaceutically-acceptable carrier is “acceptable” in the sense ofbeing compatible with the other ingredients of the composition and notdeleterious to the recipient thereof. The pharmaceutically-acceptablecarriers employed herein may be selected from various organic orinorganic materials that are used as materials for pharmaceuticalformulations and which are incorporated as analgesic agents, buffers,binders, disintegrants, diluents, emulsifiers, excipients, extenders,glidants, solubilizers, stabilizers, suspending agents, tonicity agents,vehicles and viscosity-increasing agents. Pharmaceutical additives, suchas antioxidants, aromatics, colorants, flavor-improving agents,preservatives, and sweeteners, may also be added. Examples of acceptablepharmaceutical carriers include carboxymethyl cellulose, crystallinecellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powders, saline, sodium alginate, sucrose, starch, talc andwater, among others. In some embodiments, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. When administered to a subject, the compound andpharmaceutically acceptable carrier can be sterile. Suitablepharmaceutical carriers may also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300,water, ethanol, polysorbate 20, and the like. The present compositions,if desired, may also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents.

Surfactants such as, for example, detergents, are also suitable for usein the formulations. Specific examples of surfactants includepolyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin orsodium carboxymethylcellulose; or acrylic derivatives, such asmethacrylates and others, anionic surfactants, such as alkalinestearates, in particular sodium, potassium or ammonium stearate; calciumstearate or triethanolamine stearate; alkyl sulfates, in particularsodium lauryl sufate and sodium cetyl sulfate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids, in particular those derived from coconut oil, cationicsurfactants, such as water-soluble quaternary ammonium salts of formulaN⁺A′R″R′″R″″Y⁻, in which the R radicals are identical or differentoptionally hydroxylated hydrocarbon radicals and Y⁻ is an anion of astrong acid, such as halide, sulfate and sulfonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used, amine salts of formula N⁺A′R″R′″, in which the R radicalsare identical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used, non-ionic surfactants, such as optionallypolyoxyethylenated esters of sorbitan, in particular Polysorbate 80, orpolyoxyethylenated alkyl ethers; polyethylene glycol stearate,polyoxyethylenated derivatives of castor oil, polyglycerol esters,polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids orcopolymers of ethylene oxide and of propylene oxide, amphotericsurfactants, such as substituted lauryl compounds of betaine and thelike.

The pharmaceutical formulations of the present technology are preparedby methods well-known in the pharmaceutical arts. Optionally, one ormore accessory ingredients (e.g., buffers, flavoring agents, surfaceactive agents, and the like) also are added. The choice of carrier isdetermined by the solubility and chemical nature of the compounds,chosen route of administration and standard pharmaceutical practice.

Such compositions can be formulated for different routes ofadministration. Although compositions suitable for oral delivery willprobably be used most frequently, other routes that may be used includetransdermal, intravenous, intraarterial, pulmonary, rectal, nasal,vaginal, lingual, intramuscular, intraperitoneal, intracutaneous,intracranial, and subcutaneous routes. Suitable dosage forms foradministering any of the compounds described herein include tablets,capsules, pills, powders, aerosols, suppositories, parenterals, and oralliquids, including suspensions, solutions and emulsions. Sustainedrelease dosage forms may also be used, for example, in a transdermalpatch form. All dosage forms may be prepared using methods that arestandard in the art (see e.g., Remington's Pharmaceutical Sciences, 16thed., A. Oslo editor, Easton Pa. 1980).

The compounds and/or compositions of the present technology areadministered to a human or animal subject by known procedures includingoral administration, sublingual or buccal administration. In someembodiments, the compound or composition is administered orally.

For oral administration, a formulation of the compounds of thetechnology may be presented in dosage forms such as capsules, tablets,powders, granules, or as a suspension or solution. Capsule formulationsmay be gelatin, soft-gel or solid. Tablets and capsule formulations mayfurther contain one or more adjuvants, binders, diluents, disintegrants,excipients, fillers, or lubricants, each of which are known in the art.Examples of such include carbohydrates such as lactose or sucrose,dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol,cellulose or derivatives thereof, microcrystalline cellulose, gelatin,stearates, silicon dioxide, talc, sodium starch glycolate, acacia,flavoring agents, preservatives, buffering agents, disintegrants, andcolorants.

Compounds and pharmaceutical compositions described herein may be usedalone or in combination with other compounds. When administered withanother agent, the co-administration can be in any manner in which thepharmacological effects of both are manifest in the patient at the sametime. Thus, co-administration does not require that a singlepharmaceutical composition, the same dosage form, or even the same routeof administration be used for administration of both the CNE compounddescribed herein and the other agent or that the two agents beadministered at precisely the same time. However, co-administration willbe accomplished most conveniently by the same dosage form and the sameroute of administration, at substantially the same time. Obviously, suchadministration most advantageously proceeds by delivering both activeingredients simultaneously in a novel pharmaceutical composition inaccordance with the present technology.

In some embodiments, the technology relates to novel cannabinoidreceptor modulators, and uses thereof for treating diseases, conditionsand/or disorders modulated by a cannabinoid receptor.

In one aspects, a method is provided for treating a condition modulatedby CB1, CB2 receptors and/or the GPR55 receptor activity, the methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of any of the compounds or compositions describedherein.

In some embodiments, the compounds show a high affinity for at least oneof the cannabinoid receptors, CB1, CB2 or GPR55. Thus, another aspect ofthe technology is use of at least one of the compounds to interact witha cannabinoid receptor, CB1, CB2 or GPR55.

In some embodiments, the CNE compounds disclosed herein show a highaffinity for more than one of the cannabinoid receptors, CB1, CB2 orGPR55. Thus, another aspect of the technology is use of the CNEcompounds to interact with more than one of cannabinoid receptor, CB1,CB2 or GPR55.

In some embodiments, a method of agonizing and/or antagonizing orinhibiting activity of cannabinoid 1 (CB1), cannabinoid 2 (CB2) or GPR55receptors is provided. The method includes contacting the cannabinoid 1(CB1), cannabinoid 2 (CB2) or GPR55 receptors with a compound comprisinga nitrate ester moiety. In some embodiments, a compound comprising anitrate ester moiety includes any of the compounds or compositionsdescribed herein.

In some embodiments, provided is the use of a cannabinoid receptoragonist or a cannabinoid receptor antagonist for the manufacture of amedicament for the treatment of a condition modulated by CB1, CB2receptors and/or the GPR55 receptor activity, wherein the cannabinoidreceptor agonist or antagonist is compound comprising a nitrate estermoiety. In some embodiments, a compound comprising a nitrate estermoiety includes any of the compounds or compositions described herein.In some embodiments, the compound comprising a nitrate ester moeity isan agonist of antagonist of CB1, CB2 or GPR55 receptors and combinationsthereof. In some embodiments, the compound comprising a nitrate estermoeity is a full agonist, a partial agonist, a neutral agonist, aninverse agonist, a full antagonist, a partial antagonist, a neutralantagonist, or an inverse antagonist. In certain embodiments, thecannabinoid receptor inverse agonist or cannabinoid receptor neutralantagonist is a CB1 inverse agonist or a CB1 neutral antagonist or a CB2inverse agonist or a CB2 neutral antagonist.

In some embodiments, the compound exhibit fluorescent properties. Thefluorescent compounds are typically endogenously fluorescent and do notrely on linking the cannabinoid compound to a fluorescent moiety.

In certain embodiments, the compound is covalently linked via a linkerto an immmunogen such as Bovine Serum Albumin, polypeptides orpolysaccharides in order to produce a physiological effect.

In some embodiments, the compounds interact with the cannabinoidreceptors present in the CNS without affecting the receptors in theperiphery to the same degree. Therefore, still another aspect of thetechnology is use of the CNE compounds to preferentially interact withcannabinoid receptors present either in the CNS or the periphery. Insome embodiments, the CNE compounds affect the receptors in theperiphery as well as in the CNS. Therefore, still another aspect of thetechnology is use of at least one of the CNE compounds that affect thereceptors in the periphery without substantially affecting the receptorsin the CNS.

The compounds described herein, and pharmaceutically acceptable saltsthereof, have pharmacological properties when administered intherapeutically effective amounts for providing a physiologicalresponse. Thus, another aspect of the technology is the administrationof a therapeutically effective amount of the CNE compounds, or apharmaceutically acceptable salt thereof, to a subject to provide aphysiological response.

In some embodiments, a “therapeutically effective amount” of a compound,is the quantity of a compound which, when administered to a subject,results in a sufficiently high level of that compound in the subject tocause a physiological response, for example a discernible increase ordecrease in stimulation of cannabinoid receptors. The compoundsdescribed herein, and pharmaceutically acceptable salts thereof, havepharmacological properties when administered in therapeuticallyeffective amounts individually or in combination for providing aphysiological response useful to treat CNS neuro-inflammation,inflammatory pain, peripheral neuropathic pain associated withallodynia, autoimmune diabetes, obesity, diabetes, metabolic syndrome,metabolic disorders including cardiovascular disorders, diabeticnephropathy, cardiomyopathy including diabetic cardiomyopathy, sexualbehavior, inflammatory bowel disease and other gastrointestinal allergicdisorders including colonic inflammation, nausea and vomiting associatedwith cancer chemotherapy, rheumatoid arthritis, atopic dermatitis,psoriasis, autoimmune disorders including diabetes, angiogenesis,anorexia and weight loss in patients with AIDS, HIV-Wasting syndrome,HIV neuropathy, cervical dystonia, chronic pain in patients with acutecomplex regional pain syndromes, fibromyalgia, atherosclerosis,convulsions, cancer including cancers of the immune system, diabeticneuropathic pain, inflammatory nociception, nociception in persistentpain states, mesentery pain, amyotrophic lateral sclerosis, braintumors, Tourette's syndrome, intraocular pressure, treatment of crampsduring amyotrophic lateral sclerosis, non-GERD related non-cardiac chestpain, trichotillomania, interstitial cystitis, experimental colitis,wound healing, hepatic encephalopathy, liver cirrhosis, hepatitis,graft-versus-host-disease, insomnia, inflammatory hyperalgesia, tissueanoxia and related illness, europathic nociception and pain duringcancer chemotherapy, chronic obstructive lung disease, postherpeticneuralgia, chronic pain which includes lower-back pain, brachial plexusinjury, phantom limb pain, pain of neurological origin, asthma,osteoarthritis, chronic respiratory diseases, allergic diseasesincluding allergic asthma, anorexia nervosa, cachexia, orexigenictherapy in advanced cancer patients with chemosensory abnormalities,primary gliomas, neuronal damage due to hyperglycemia, angiogenesis,gastrointestinal conditions and osteoporosis, persistent abdominal pain,postsurgical abdominal pain, sleep apnea, headache, migraine, glaucomaor ocular hypertension, epilepsy, stress, Crohn's disease, systemiclupus erythematosus, renal ischemia, lower urinary tract dysfunction,overactive bladder, detrusor overactivity, nephritis, psychosomaticdisorders, thymic disorders, dyskinesia, kinetic disorder, anxietydisorders, psychotic disorders, cognitive disorders, appetite disorders,mood disorders, bipolar affective disorder, delirious disorders, benignprostatic hyperplasia, angina pectoris, anal fissure, chronicneuroinflammatory conditions, acute radiation toxicity,neurodegeneration, posttraumatic stress disorders, multiple sclerosis,central neuropathic pain in multiple sclerosis, detrusor overactivity inpatients with multiple sclerosis, spasticity in multiple sclerosis,Alzheimer's disease, Huntington's disease, pro-neurogenic effects inareas of adult neurogenesis, neurotoxicity, sedation during outpatientsurgical procedures, scleroderma, post-surgical pain, reduction ofsecondary damage following acute injury and neurodegenerative eventssuch as depression, prevent rejection of foreign tissue during organtransplant, schizophrenia, obsessive-compulsive disorder, stroke,seizures, toxin exposure, ischemia, hypoxia, traumatic brain injury,comatose conditions, spinal cord injury, ischemic brain damage, fattyliver, Rett syndrome, cannabis dependence, alcohol, opioid, nicotinecocaine addiction and dementia. Additionally, these analogs can beuseful in cancer chemotherapy. Typically, a “therapeutically effectiveamount” of an compound is believed to range from about 0.01 mg/day toabout 1,000 mg/day.

In some embodiments, the compounds disclosed in the technology can beused in combination with other acceptable pharmaceutical substances. Aswill be apparent, the compounds of the technology can be used alone orin combination with other well-known agents, isomers thereof andpharmaceutically acceptable salts thereof, such asΔ⁹-tetrahydrocannabinol, nabilone, Δ⁸-tetrahydrocannabinol,(+)-cannabidiol, (−)-cannabidiol, Δ⁸-tetrahydrocannabivarin,Δ⁹-tetrahydrocannabivarin, CP-47,497, Cannabidivarin, dexanabinol,Ajulemic acid, HU-210, 8-β-OH-tetrahydrocannabinol,8-α-OH-tetrahydrocannabinol, SAB-378, nabitan, mcnabitan, A-40174, Org28611, nonabine, BAY38-7271, GRC10693, S-777469, AZD¹940, GW-842,166X,GW-405,833, levonantradol, dimethylheptylpyran, AM1710, PRS-211,375,JD-5037, AM6545,5-(4-(4-cyanobut-1-yn-1-yl)phenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-morpholino-1H-pyrazole-3-carboxamide,5-(4-(4-cyanobut-1-yn-1-yl)phenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide,MePPEP, AM10009, AM10027, AM1241, A-796260, A-836339, Xenical®(Orlistat), Meridia® (Sibutramine), Phentermine, SR147778 (Surinabant),AVE-1625, CP-945,598 (Otenabant), Qnexa®, Contrave, Empatic, rosonabant,lorcaserin, MK-0364 (Taranabant), SLV-319 (Ibipinabant), JD5037, JD-5006and SR141716A (Acomplia®/Rimonabant).

In some embodiments, compounds of the technology can also be used incombination with a CNS active CB1 neutral antagonist, peripherallyrestricted CB1 neutral antagonist, CNS active CB1 inverse agonist,peripherally restricted CB1 inverse agonist, opioid agonist, opioidantagonist, vanilloid receptor agonist, non-steroidal anti-inflammatorydrug, approved local anesthetic, CB2 agonist, CB1 agonist, CB1 and CB2mixed agonist, α2-adrenoceptor agonist, dopamine receptor agonist,adenosine receptor agonist, neurotensin receptor agonist, thyroxinederivative, cytochrome c inhibitor, oxygen tension reducer, GABA, acholinergic drug, a nucleoside drug, serotoninergic agent, NMDA receptorantagonist, potassium channel modulator, anticonvulsant agent,contraceptive agent, an allosteric modulator, antipsychotic agent, animmunosuppressive agent, anticonstipation agent and/or acyclooxygenase-2 inhibitor. In some embodiments, this combinationcomprising the two pharmaceutically active ingredients can be in ratiosranging from 1:99 to 99:1. In some embodiments, this combination cancomprise three pharmaceutically active ingredients in safe acceptableratios that can cause a physiological response.

In some embodiments, any of the CNE compound disclosed herein could initself act as a drug with a combination effect. For example compoundsdisclosed in the technology could dually act as a CB2 agonist as well asCB1 antagonist.

In some embodiments, the CNE compounds disclosed herein could exist invarious solid forms. The solid forms can be crystalline or amorphousforms including, but not limited to, solvates, hydrates, and N-oxides.These solid forms can be obtained by treating either the free base ortheir salts at a certain adjusted pH and certain temperature with asolvent or a combination of solvents. The solvents can be, for example,a hydrocarbon solvent such as toluene, xylene, hexanes, heptane, orpetroleum ether, alcohol such as methanol, ethanol, n-butanol,n-propanol and 2-propanol, di-isopropyl ether, ethyl-acetate,dichloromethane, acetic acid, acetone, tetrahydrofuran, dichloromethane,and water.

In some embodiments, the CNE compounds exist as isomers comprising ofconstitutional isomers and stereoisomers including enantiomers,diastereomers, geometric isomers, racemates, tautomers, rotamers, oratropisomers.

In some embodiments, compounds disclosed herein are nitric oxide donors.

In some embodiments, compounds disclosed herein produce long lastingduration of action as they form a covalent bond to the cannabinoidreceptors.

In some embodiments, the compounds disclosed herein act covalently onthe receptors.

In some embodiments, compounds disclosed herein are capable of labelingthe amino acid residues within the cannabinoid receptor. Examples of theamino acid residues include, but are not limited to, cystines, serines,and tyrosines.

In some embodiments, compounds disclosed herein have a prolonged andextended duration of action. In some embodiments, compounds disclosedherein have a drug residence time ranging from 60 minutes to 340 hours.

The compounds of the present technology can be administered by a varietyof known methods, including orally, rectally, or by parenteral routes(e.g., intramuscular, intravenous, subcutaneous, nasal or topical). Theform in which the compounds are administered will be determined by theroute of administration. Such forms include, but are not limited to,capsular and tablet formulations (for oral and rectal administration),liquid formulations (for oral, intravenous, intramuscular, subcutaneous,ocular, intranasal, inhalation-based and transdermal administration) andslow releasing microcarriers (for rectal, intramuscular or intravenousadministration). The formulations can also contain a physiologicallyacceptable vehicle and optional adjuvants, flavorings, colorants andpreservatives. Suitable physiologically acceptable vehicles include, forexample, saline, sterile water, Ringer's solution and isotonic sodiumchloride solutions. The specific dosage level of active ingredient willdepend upon a number of factors, including, for example, biologicalactivity of the particular preparation, age, body weight, sex andgeneral health of the individual being treated.

The overall therapeutic opportunities available throughcannabinoid-related medications individually or as combination therapyare very diverse and include CNS neuro-inflammation, inflammatory pain,peripheral neuropathic pain associated with allodynia, autoimmunediabetes, obesity, diabetes, metabolic syndrome, metabolic disordersincluding cardiovascular disorders, diabetic nephropathy, cardiomyopathyincluding diabetic cardiomyopathy, acute radiation toxicity, sexualbehavior, inflammatory bowel disease and other gastrointestinal allergicdisorders including colonic inflammation, nausea and vomiting associatedwith cancer chemotherapy, rheumatoid arthritis, atopic dermatitis,psoriasis, autoimmune disorders including diabetes, scleroderma,systemic lupus erythematosus, angiogenesis, anorexia and weight loss inpatients with AIDS, HIV-Wasting syndrome, HIV neuropathy, cervicaldystonia, chronic pain in patients with acute complex regional painsyndromes, fibromyalgia, atherosclerosis, convulsions, trichotillomania,interstitial cystitis, wound healing, colitis, cancer including cancersof the immune system, diabetic neuropathic pain, inflammatorynociception, nociception in persistent pain states, mesentery pain,amyotrophic lateral sclerosis, brain tumors, treatment of cramps duringamyotrophic lateral sclerosis, non-GERD related non-cardiac chest pain,hepatic encephalopathy, liver cirrhosis, hepatitis,graft-versus-host-disease, insomnia, inflammatory hyperalgesia, tissueanoxia and related illness, europathic nociception and pain duringcancer chemotherapy, chronic obstructive lung disease, post-therpeticneuralgia, chronic pain which includes lower-back pain, brachial plexusinjury, phantom limb pain, pain of neurological origin, asthma,osteoarthritis, chronic respiratory diseases, allergic diseasesincluding allergic asthma, anorexia nervosa, cachexia, orexigenictherapy in advanced cancer patients with chemosensory abnormalities,primary gliomas, neuronal damage due to hyperglycemia, angiogenesis,gastrointestinal conditions and osteoporosis, persistent abdominal pain,post-surgical abdominal pain, sleep apnea, headache, migraine, glaucomaor ocular hypertension, epilepsy, stress, Crohn's disease, renalischemia, lower urinary tract dysfunction, overactive bladder, detrusoroveractivity, nephritis, psychosomatic disorders, thymic disorders,dyskinesia, kinetic disorder, anxiety disorders, psychotic disorders,cognitive disorders, appetite disorders, mood disorders, bipolaraffective disorder, delirious disorders, benign prostatic hyperplasia,angina pectoris, anal fissure, chronic neuroinflammatory conditions,neurodegeneration, post-traumatic stress disorders, multiple sclerosis,central neuropathic pain in multiple sclerosis, detrusor overactivity inpatients with multiple sclerosis, spasticity in multiple sclerosis,ischemic brain damage, Alzheimer's disease, Huntington's disease,pro-neurogenic effects in areas of adult neurogenesis, neurotoxicity,sedation during outpatient surgical procedures, post-surgical pain,reduction of secondary damage following acute injury andneurodegenerative events such as depression, prevent rejection offoreign tissue during organ transplant, schizophrenia,obsessive-compulsive disorder, stroke, seizures, toxin exposure,ischemia, hypoxia, traumatic brain injury, spinal cord injury, fattyliver, Rett syndrome, cannabis dependence, alcohol, opioid, nicotinecocaine addiction and dementia.

In addition to the CB1 and CB2 receptors, recently, GPR55 has been newlyidentified as a putative cannabinoid (or “CB3”) receptor and ade-orphanized δ type GPCR that belongs to group of the rhodopsin-likereceptors. GPR55 has high levels of expression in the human striatum,visceral and subcutaneous adipose tissue, as well as in the liver, andshows low sequence identity to both CB1 (13.5%) and CB2 (14.4%)receptors. GPR55 is activated by the by the only known endogenous lipidligand L-α-lysophosphatidylinositol (LPI). In addition several CB1 andCB2 ligands are known to be recognized by GPR55 as antagonists, some ofwhich are Δ⁹-THC, cannabidiol, and Abnormal-cannabidiol, all with veryweak affinity. Though the physiological function of GPR55 in vivoremains largely unknown, and it was recently shown that the LPI/GPR55system is positively associated with obesity in humans. As having apotential role in inflammation, it has been suggested that GPR55 andCB2R interfere with each other's signaling pathways in a way such thatCB2-mediated responses are modulated. It has also been shown that GPR55mediates the effects of LPI in prostate and ovarian cancer cells aswell. Evidence continues to suggest that elevated levels of GPR55 andLPI present in most cancer cells can promote oncogenecity. Due to thetherapeutic potential of GPR55 of this magnitude, efforts are beingdevoted in finding GPR55 compounds that deactivate the receptor and slowthe progression of cancer cells. In addition, the GPR55 receptor hasbeen implicated in conditions such as anorexia nervosa, angiogenesis,gastrointestinal conditions and osteoporosis.

Nitric Oxide “NO” is a ubiquitous signaling molecule within the humanphysiology that is able to diffuse readily across cell membranes andmodulate a myriad of biological responses such as geneinduction/activation, apoptosis, cytostasis, immune stimulation,platelet inhibition, smooth muscle relaxation. NO is known to play acritical role in the prevention and repair of injury to gastrointestinal(GI) tissue and perhaps acting as a local anti-inflammatory agent and acomplement to gastroprotective prostaglandins. NO effectively reducesgastric mucosal injury and facilitates GI healing following chemicalinsult and is therefore considered a prime therapeutic candidate forreducing NSAID-induced GI toxicity. Historically, NO is known to be themost potent endogenous vasodilator and has proven to be beneficial intreating cardiovascular diseases. The NO-producing therapeutic andnitrovasodilator glyceryl trinitrate (“nitroglycerine”) was among thefirst compounds used to treat coronary atherosclerosis accompanied byhypertension and chest pain (“angina”) in patients with ischemicheart-disease. Organic nitrate esters (R—ONO₂) are NO donating compoundsand when the ONO₂ functional group is tethered to an activepharmaceutical substance, may enhance and improve some of itspharmacological and phyisicochemical features. Commonly used andproposed organic nitrate based medications that can also act as NOdonors include isosorbide dinitrate, isosorbide mononitrate, nicorandiland naproxcinod. In addition to reducing GI toxicity, importanttherapeutic areas for organic nitrate ester based therapies includeangina pectoris, anal fissure, erectile dysfunction, osteoarthritis andneuroprotection.

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures described in this disclosure. It is to beunderstood that the examples are provided to illustrate certainembodiments and that no limitation to the scope of the disclosure isintended thereby. It is to be further understood that resort may be hadto various other embodiments, modifications, and equivalents thereofwhich may suggest themselves to those skilled in the art withoutdeparting from the spirit of the present disclosure and/or scope of theappended claims.

It will be recognized that one or more features of any embodimentsdisclosed herein may be combined and/or rearranged within the scope ofthe technology to produce further embodiments that are also within thescope of the technology.

EXAMPLES Example 1: Synthesis of Compound 1

Step 1: To a flask containing(6aR,10aR)-3-(6-bromo-2-methylhexan-2-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol(2, 300 mg, 0.71 mmol) (prepared as in AAPS J. 2004 Oct. 19; 6(4):e30and procedures based on J. Med. Chem. 1984, 27, 67-7; hereinincorporated by reference in its entirety)) is added sodium iodide (320mg, 2.13 mmol) and acetone (25 ml) and the contents are refluxed for 3hours. The solvent is evaporated in vacuo and the residue is taken indichloromethane (25 ml), washed with water (2×25 ml), dried over MgSO₄and then purified by column chromatography to afford the iodo derivative3 as a dark brown syrup (200 mg, 60%): ¹H NMR (500 MHz, CDCl₃) δ 6.38(d, J=1.46 Hz, 1H), 6.22 (d, J=0.98 Hz, 1H), 5.44 (br. s., 1H), 4.67 (s,1H), 3.15-3.23 (dd, 1H), 3.12 (t, J=7.08 Hz, 2H), 2.61-2.78 (td, 1H),2.08-2.28 (m, 1H), 1.75-1.97 (m, 3H), 1.59-1.67 (m, 2H), 1.51-1.58 (m,5H), 1.40 (s, 3H), 1.23 (s, 6H), 1.14-1.20 (m, 2H), 1.12 (s, 3H); MS(ESI⁺) for m/z 469 (M+H).

Step 2:(6aR,10aR)-3-(6-iodo-2-methylhexan-2-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol,3 obtained from the previous step is suspended in acetonitrile (20 ml)and to it silver nitrate (217 mg, 1.28 mmol) is added and the contentsare heated to 70° C. for 1 hour. The solvents are evaporated in vacuoand the residue is suspended in dichloromethane (25 ml), washed withwater (2×25 ml), dried over MgSO₄ and then purified by columnchromatography to afford5-((6aR,10aR)-1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-5-methylhexylnitrate as a yellow syrup (Compound 1, 89 mg, 52%): ¹H NMR (500 MHz,CDCl₃) δ 6.38 (d, J=1.46 Hz, 1H), 6.22 (d, J=1.46 Hz, 1H), 5.45 (br. s.,1H), 4.67 (s, 1H), 4.38 (t, J=6.84 Hz, 2H), 3.19 (dd, J=4.64, 16.85 Hz,1H), 2.70 (td, J=5.55, 10.86 Hz, 1H), 2.08-2.28 (m, 1H), 1.75-1.97 (m,3H), 1.59-1.67 (m, 2H), 1.51-1.58 (m, 5H), 1.40 (s, 3H), 1.23 (s, 6H),1.14-1.20 (m, 2H), 1.12 (s, 3H); MS (ESI⁺) for m/z 404 (M+H).

Example 2: Synthesis of Compound 10

Step 1: To a mixture of 2-(3,5-dimethoxyphenyl)-2-methyl-8-phenoxyoctane(4, 10 mmol, prepared as in AAPS J. 2004 Oct. 19; 6(4):e30, andprocedures based on J. Med. Chem. 1984, 27, 67-71, herein incorporatedby reference in its entirety) in CCl₄ (35 ml) is added a solution of Br₂(10 mmol) in CCl₄ (4 ml) during 2 h at 0° C. (procedures adopted from J.Chem. Soc., Perkin Trans. 2, 1997, 2219-2228, herein incorporated byreference in its entirety). After addition the solution is stirred for 1h at 0° C. followed by evaporation to dryness to give compound 5.

Step 2: To a stirred solution of2-bromo-1,3-dimethoxy-5-(2-methyl-8-phenoxyoctan-2-yl)benzene (5, 8.0mmol) in anhydrous THF (40 ml) under an argon atmosphere at −78° C. isadded n-BuLi (8.8 mmol using 1.6 M solution in hexane) over a 30 minperiod. Stirring is continued at −78° C. for 15 min and then trimethylborate (24 mmol) is added (procedures adopted from WO 2008013963, hereinincorporated by reference in its entirety). Following addition, thereaction mixture is allowed to warm to room temperature over 12 hoursperiod. The pH is adjusted to 6.5 by addition of 5% aqueous HCl solutionat 0° C., and the mixture is extracted with DCM. The organic layer iswashed with brine, dried over MgSO₄ and the solvent is evaporated underreduced pressure. The residue is purified by flash column chromatographyon silica gel to give compound 6.

Step 3: To a solution of(2,6-dimethoxy-4-(2-methyl-8-phenoxyoctan-2-yl)phenyl)boronic acid (6, 1mmol) in anhydrous DCM (15 mL) is added boron tribromide (1.2 mmol) at−78° C. under nitrogen atmosphere. The resulting solution is stirred for15 minutes at −78° C. The cooling bath is removed and the reactionmixture is continued to stir for 30 minutes at room temperature. Thereaction is quenched with anhydrous methanol (1 mL) at −78° C.,concentrated in vacuo to dryness. The desired corresponding o-hydroxyboronic acid 7 is carried to the next step without further purification(procedures adopted from J. Comb. Chem. 2010, 12, 664-669, hereinincorporated by reference in its entirety).

Step 4: A solution of methyl 2-bromo-4-methoxybenzoate (8, prepared asdescribed in WO 2010033643, herein incorporated by reference in itsentirety) (0.5 mmol),(4-(8-bromo-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)boronic acid (7,0.65 mmol), cesium carbonate (2 mmol) in a mixture of dimethoxyethane (5mL) and water (0.75 mL) is degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (O) (10 mol %) is added, the reaction tubeis sealed. The reaction is heated in a microwave (Emrys optimizer fromPersonal Chemistry) at 125° C. (power 300 W) for 15 minutes. Aftercooling at room temperature, the reaction mixture is diluted with water(30 mL), extracted with DCM (2×15 mL). The combined organic layers arepassed through a phase separator and concentrated in vacuo. The residueis purified using WATERS preparative LC/MS autopurification system toafford the title compound 9 (procedures adopted from J. Comb. Chem.2010, 12, 664-669, herein incorporated by reference in its entirety).

Step 5:3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-9-methoxy-6H-benzo[c]chromen-6-one(9, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford7-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate (Compound 10).

Example 3: Synthesis of Compound 13

Step 1: To a solution of3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-9-methoxy-6H-benzo[c]chromen-6-one(9, 1.0 mmol) obtained from scheme 2 in anhydrous THF (20 mL) is addedmethylmagnesium iodide (3 mmol, 3.0 M in Et₂O) at room temperature underan argon atmosphere. The reaction mixture is stirred at room temperaturefor 30 min and then refluxed for 1.5 h. The reaction is cooled to roomtemperature and quenched by the addition of 20 mL of saturated aqueousNH₄Cl. The THF is removed and the residue is dissolved in anhydrous Et₂O(50 mL). The ether solution is washed with water and brine, dried overMgSO₄, and the solvent is evaporated to give the crude product 11(procedures adopted from J. Med. Chem. 2007, 50, 6493-6500 and J. Med.Chem, 1973, 16 (11), 1200-1206; each herein incorporated by reference inits entirety).

Step 2: Without further purification4-(8-bromo-2-methyloctan-2-yl)-2′-(2-hydroxypropan-2-yl)-5′-methoxy-[1,1′-biphenyl]-2,6-diol(11) is dissolved in anhydrous CHCl₃ (10-15 mL) and catalytic ofp-toluenesulfonic acid monohydrate is then added under an argonatmosphere. The reaction mixture is stirred at room temperature for 6-8h and then treated with 10 mL of water. The organic phase is separatedand washed with water, 15% aqueous NaHCO₃, water and brine, dried overMgSO4, the solvent evaporated and the residue is purified by columnchromatography to afford 12 (procedures adopted from J. Med. Chem. 2007,50, 6493-6500 and J. Med. Chem., 1973, 16 (11), 1200-1206; each hereinincorporated by reference in its entirety).

Step 3:3-(8-bromo-2-methyloctan-2-yl)-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-1-ol(12, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(217 mg, 1.28 mmol) is added and the contents are heated to 70° C. for 1hour. The solvents are evaporated in vacuo and the residue is taken inDCM (25 ml), washed with water (2×25 ml), dried over MgSO₄ and thenpurified by column chromatography to afford7-(1-hydroxy-9-methoxy-6,6-dimethyl-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate (Compound 13).

Example 4: Synthesis of Compound 18

Step 1: To a suspension of (methoxymethyl)triphenylphosphonium chloride(14, 4.3 mmol, dried at 60° C./0.1 mmHg for 1 h) in 25 mL of benzene isadded sodium tert-amylate (5.0 mL, 4.3 mmol; 0.85 M solution inbenzene), and the mixture is stirred at room temperature for 15 minuntil a clear, deep red solution is obtained. A solution of(6aR,10aR)-3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-7,8,10,10a-tetrahydro-6H-benzo[c]chromen-9(6aH)-one(1.5 mmol, prepared as in WO 2003005960; herein incorporated byreference in its entirety) in 15 mL of benzene is added dropwise to theylide, and the reaction stirred at 70° C. for 3 h. The reaction isquenched by drop wise addition of saturated aqueous NH₄Cl and dilutedwith 40 mL of ether and the organic phase separated. The aqueous phaseis extracted with of ether, the combined ethereal extracts are driedover MgSO₄, and the solvent is evaporated and the residue is purified byflash chromatography to give 15 (mixture of geometric isomers)(procedures adopted from J. Med. Chem. 1996, 39, 3790-3796, hereinincorporated by reference in its entirety).

Step 2: To a solution of(6aR,10aR)-3-(8-bromo-2-methyloctan-2-yl)-9-(methoxymethylene)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol(15, 0.57 mmol) in 34 mL of DCM is added aqueous trichloroacetic acid(1.96 mmol), and the solution is stirred for 10 min at room temperature.The reaction is quenched by addition of saturated aqueous NaHCO₃, washedwith brine, and dried (K₂CO₃) and the solvent evaporated. ¹H NMRspectrum of the crude product indicated the formation of aldehyde. Thecrude product is dissolved in 20 mL of absolute ethanol and stirred withanhydrous K₂CO₃ (1.14 mmol) for 24 h at room temperature. Examination ofan aliquot by ¹H NMR showed that epimerization is complete (proceduresadopted from J. Med. Chem. 1996, 39, 3790-3796, herein incorporated byreference in its entirety) to give the β-aldehyde 16.

Step 3: To a solution of(6aR,9R,10aR)-3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-9-carbaldehyde(16, 0.42 mmol) in 42 mL of absolute ethanol at 0° C. is added 63 mg ofNaBH₄ (1.68 mmol). The mixture is warmed to room temperature, stirredfor 2 h, and then quenched by drop wise addition of saturated aqueousNH₄Cl and the solvent is evaporated. The residue is dissolved in waterand extracted with ethyl acetate. The combined organic extracts arewashed with brine and dried over MgSO₄, and the solvent is evaporatedand the residue is purified by flash chromatography to give 17(procedures adopted from J. Med. Chem. 1996, 39, 3790-3796, hereinincorporated by reference in its entirety).

Step 4: To a flask containing(6aR,9R,10aR)-3-(8-bromo-2-methyloctan-2-yl)-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-01(17, 0.71 mmol) is added sodium iodide (2.13 mmol) and acetone (25 ml)and the contents are refluxed for 3 hours. The solvent is evaporated invacuo and the residue is taken in DCM (25 ml), washed with water (2×25ml), dried over MgSO₄ and then purified by column chromatography toafford the iodo compound.

Step 5:(6aR,9R,10aR)-3-(8-iodo-2-methyloctan-2-yl)-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol(1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate (1.28mmol) is added and the contents are heated to 70° C. for 1 hour. Thesolvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford7-((6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate (Compound 18).

Example 5: Synthesis of Compound 19

Step 1: To a flask containing3-(5-bromopentyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(14, 0.71 mmol, prepared a J. Med. Chem. 2005, 48, 7389-7399, hereinincorporated by reference in its entirety) is added sodium iodide (2.13mmol) and acetone (25 ml) and the contents are refluxed for 3 hours. Thesolvent is evaporated in vacuo and the residue is taken in DCM (25 ml),washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford the iodo derivative.

Step 2:3-(5-iodopentyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(1 momol) is taken in acetonitrile (20 ml) and to it silver nitrate (217mg, 1.28 mmol) is added and the contents were heated to 70° C. for 1hour. The solvent are evaporated in vacuo and the residue is taken inDCM (25 ml), washed with water (2×25 ml), dried over MgSO₄ and thenpurified by column chromatography to afford5-(1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-3-yl)pentylnitrate (Compound 19).

Example 6: Synthesis of Compounds 23 and 26

Step 1: Using known procedures (adopted from U.S. Pat. No. 5,440,052, US2007060636 and J. Med. Chem. 1994, 37, 3867-3870, herein incorporated byreference in its entirety), the 6aS,10aS isomer compound 21 and the6aR,10aR isomer compound 24 of3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl)methylpivalate are prepared starting from((1S,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methylpivalate or(1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methylpivalate and 5-(8-bromo-2-methyloctan-2-yl)benzene-1,3-diol (20,prepared as in prepared as in AAPS J. 2004 Oct. 19; 6(4):e30 andprocedures based on J. Med. Chem. 1984, 27, 67-71; each hereinincorporated by reference in its entirety).

Step 2: To a solution of compound 20 or 23 (0.955 mmol) in anhydrous DCM(9.5 mL) is added 1M solution of DIBAL-H in toluene (2 mmol) dropwise at−78° C. The reaction mixture is stirred for 2.5 h and then quenched bydrop wise addition of potassium sodium tartrate (10% solution in water)at −78° C. The reaction contents are warmed to room temperature,extracted with ethyl acetate and the organic layer is dried over MgSO₄.The crude product is purified by flash chromatography to give thecorresponding 6aS,10aS isomer 22 or the 6aR,10aR isomer 25.

Step 3: To a flask containing the 6aS,10aS isomer 22 or the 6aR,10aRisomer 25 of3-(8-bromo-2-methyloctan-2-yl)-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol(0.71 mmol) is added sodium iodide (2.13 mmol) and acetone (25 ml) andthe contents are refluxed for 3 hours. The solvent is evaporated invacuo and the residue is taken in DCM (25 ml), washed with water (2×25ml), dried over MgSO₄ and then purified by column chromatography toafford the iodo compound.

Step 3: The 6aS,10aS isomer or the 6aR,10aR isomer of3-(8-iodo-2-methyloctan-2-yl)-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-olis taken in acetonitrile (20 ml) and to it silver nitrate (1.28 mmol) isadded and the contents are heated to 70° C. for 1 hour. The solvent isevaporated in vacuo and the residue is taken in DCM (25 ml), washed withwater (2×25 ml), dried over MgSO₄ and then purified by columnchromatography to afford the 6aS,10aS isomer (compound 23) or the6aR,10aR isomer of7-((6aS,10aS)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate (compound 26).

Example 7: Synthesis of Compound 33

Step 1: To a solution of3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-N-methylaniline (27, 25 mmol,prepared starting from 2-(tert-butyldimethylsilyloxy)ethanol and 3-nitrophenol based on procedures adopted from J. Med. Chem., 2007, 50 (20), pp4898-4908, herein incorporated by reference in its entirety) in1,2-dichloroethane (25 mL) is added dichlorophenylborane (25 mmol) at 0°C. The resulting mixture is refluxed for 2 h under a rapid stream ofnitrogen to remove the HCl formed. The mixture is cooled to give thetitle compound 28 (based on procedures adopted from CA2170850, hereinincorporated by reference in its entirety).

Step 2: A solution ofN-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-1-chloro-N-methyl-1-phenylboranamine(28, 11 mmol) in 1,2-dichloroethane is added dropwise to a mixture of(R)-(±)-citronellal (29, 1.54 g, 10 mmol) and diisopropylethylamine (20mmol) in DCM at −20° C. The mixture is stirred at −20° C. for 2 h and at20° C. for 0.5 hours, quenched with ammonium acetate and then filteredthrough a short pad of silica gel. The filtrate is concentrated and theresidue is chromatographed on silica gel to give compounds 30 and 31 asdiastereomeric mixtures (based on procedures adopted from CA2170850,herein incorporated by reference in its entirety).

Step 3: A mixture of(3R)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(methylamino)phenyl)-3,7-dimethyloct-6-en-1-ol(31, 1 mmol), phenylboronic acid (3 mmol) and propionic acid (0.3 mmol)in benzene (10 mL) is refluxed for 20 h to give, after chromatographycompound 32 (based on procedures adopted from CA2170850, hereinincorporated by reference in its entirety).

Step 4: Tetrabutylammonium fluoride (0.6 mmol from a 1.0 M solution inTHF) is added under a nitrogen atmosphere to a cold solution (ice bath)of the(6aR,9R,10aR)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridine(32, 0.54 mmol) in tetrahydrofuran (THF) (3 mL). The resulting solutionis stirred at 0° C. for 15 min. Water is added, and the mixture isextracted ethyl acetate. The organic layer is dried over MgSO₄ andevaporated to give the crude product.

Step 5:2-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-3-yl)oxy)ethanol(0.33 mmol) is dissolved in anhydrous DCM (3 mL), cooled to 0° C. andtriphenylphosphine (0.26 g, 0.99 mmol) and tetrabromomethane (0.4 mL;1.41 mmol) are added. The reaction mixture is stirred for 3 h afterwhich a portion of methanol and water are sequentially added, and themixture is extracted with DCM, sequentially washed with aqueous NaS₂O₃and brine, and dried over MgSO₄. After removal of solvents, the residueis purified by silica gel column chromatography to afford the bromocompound.

Step 6: To a flask containing(6aR,9R,10aR)-3-(2-bromoethoxy)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridine(0.71 mmol) is added sodium iodide (2.13 mmol) and acetone (25 ml) andthe contents are refluxed for 3 hours. The solvent is evaporated invacuo and the residue is taken in DCM (25 ml), washed with water (2×25ml), dried over MgSO₄ and then purified by column chromatography toafford the iodo compound.

Step 7:(6aR,9R,10aR)-3-(2-iodoethoxy)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridine(1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate (217mg, 1.28 mmol) is added and the contents are heated to 70° C. for 1hour. The solvent is evaporated in vacuo and the residue is taken in DCM(25 ml), washed with water (2×25 ml), dried over MgSO₄ and then purifiedby column chromatography to afford the title compound2-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-3-yl)oxy)ethylnitrate (Compound 33).

Example 8: Synthesis of Compound 40

Step 1: To a flask containing diisopropylamine (218 mmol) is addedanhydrous THF ([0.24 M]) and the reaction is cooled to −20° C. To this asolution of n-BuLi in hexanes (solution titrated at 2.48 M) (212 mmol)is added dropwise at −20° C. and the reaction is stirred for 2 hours at−20° C. 2-(3,5-dimethoxyphenyl)acetic acid (34, 53 mmol) is dissolved inanhydrous THF and is added dropwise to the LDA solution at 20° C. Thereaction is slowly warmed to −5° C. using a brine/ice cooling bath andstirred for 2 hours at −5° C. Iodomethane (318 mmol) is then addeddropwise at −5° C. and the reaction is gradually warmed up to roomtemperature and stirred for 15 hours at room temperature. The reactionis quenched by adding 100 mL of an aqueous solution of HCl 1N anddiluted with Et₂O (200 mL). The Et₂O layer is separated and the aqueouslayer is extracted with Et₂O (3×) and the organic layers are combined,dried over MgSO₄, and evaporated to dryness. The crude acid is purifiedby flash chromatography over silica gel to give the product (procedureadopted from Nature Chemistry, 4(3), 228-234; 2012, herein incorporatedby reference in its entirety).

Step 2: To a solution 2-(3,5-dimethoxyphenyl)-2-methylpropanoic acid(35, 4.5 mmol) in dry DCM (20 mL) at room temperature are addeddicyclohexylcarbodiimide (9.0 mmol) and 4-(dimethylamino)pyridine (0.9mmol). To this is added, 3-phenoxypropan-1-ol (1.2 eq) and the resultingmixture is stirred for 12 h before it is quenched with NaHCO₃ (20 mL,sat. aq.). The layers are separated, and the aqueous layer is extractedwith Et₂O (3×20 mL). The combined organic layers are washed with brine(20 mL), dried over MgSO₄ and concentrated in vacuo. The residue ispurified by flash chromatography over silica gel to give the ester 35(procedures adopted from Chinese Journal of Chemistry, 28(6), 1041-1043;2010, herein incorporated by reference in its entirety).

Step 3: A solution of Br₂ (10 mmol) in CCl₄ (4 ml) is added to3-phenoxypropyl 2-(3,5-dimethoxyphenyl)-2-methylpropanoate (10 mmol) inCCl₄ (35 ml) during 2 h at 0° C. (procedures adopted from J. Chem. Soc.,Perkin Trans. 2, 1997, 2219-2228, herein incorporated by reference inits entirety) After addition the solution is stirred for 1 h at 0° C.followed by evaporation to dryness to give the bromo derivative 36.

Step 3: To a stirred solution of 3-phenoxypropyl2-(4-bromo-3,5-dimethoxyphenyl)-2-methylpropanoate (36, 8.0 mmol) inanhydrous THF (40 ml) under an argon atmosphere at −78° C. is addedn-BuLi (8.8 mmol using 1.6 M solution in hexane) over a 30 min period.Stirring is continued at −78° C. for 15 min and then trimethyl borate(24 mmol) is added (procedures adopted from WO 2008013963, hereinincorporated by reference in its entirety). Following addition, thereaction mixture is allowed to warm to room temperature over 12 hoursperiod. The pH is adjusted to 6.5 by addition of 5% aqueous HCl solutionat 0° C., and the mixture is extracted with DCM. The organic layer iswashed with brine, dried over MgSO₄ and the solvent is evaporated underreduced pressure. The residue is purified by flash column chromatographyon silica gel to give compound 37.

Step 4: To a solution of(2,6-dimethoxy-4-(2-methyl-1-oxo-1-(3-phenoxypropoxy)propan-2-yl)phenyl)boronicacid (37, 1 mmol) in anhydrous DCM (15 mL), is added boron tribromide(1.2 mmol) at −78° C. under nitrogen atmosphere. The resulting solutionis stirred for 15 minutes at −78° C. The cooling bath is removed and thereaction mixture is continued to stir for 30 minutes at roomtemperature. The reaction is quenched with anhydrous methanol (1 mL) at−78° C., concentrated in vacuo to dryness. The corresponding o-hydroxyboronic acid 38 is confirmed by LC/MS and is carried to the next stepwithout further purification (procedures adopted from J. Comb. Chem.2010, 12, 664-669, herein incorporated by reference in its entirety).

Step 5: A solution of methyl 2-bromo-4-methoxybenzoate (8, 0.5 mmol),(4-(1-(3-bromopropoxy)-2-methyl-1-oxopropan-2-yl)-2,6-dihydroxyphenyl)boronicacid (38, 0.65 mmol), cesium carbonate (2 mmol) in a mixture ofdimethoxyethane (5 mL) and water (0.75 mL) is degassed with argon for 5minutes. Tetrakis(triphenylphosphine)-palladium (0) (10 mol %) is added,the reaction tube is sealed. The reaction is heated in a microwave(Emrys optimizer from Personal Chemistry) at 125° C. (power 300 W) for15 minutes. After cooling, the reaction mixture is diluted with water(30 mL), acidified to pH 5, extracted with DCM (2×15 mL). The combinedorganic layers are passed through a phase separator and concentrated invacuo. The residue is purified with WATERS preparative LC/MSautopurification system to afford the title compound 39 (proceduresadopted from J. Comb. Chem. 2010, 12, 664-669, herein incorporated byreference in its entirety).

Step 6: 3-bromopropyl2-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-2-methylpropanoate(39, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford the title compound 3-(nitrooxy)propyl2-(1-hydroxy-9-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)-2-methylpropanoate (compound 40).

Example 9: Synthesis of Compound 46

Step 1: To a stirred solution of 2-(3,5-dimethoxyphenyl)-2-oxoaceticacid (41, prepared as in Journal of the American Chemical Society,132(21), 7540-7548, 2010, herein incorporated by reference in itsentirety) (15.8 mmol) in anhydrous DCM (30 mL) at room temperature isadded (diethylamino)sulfur trifluoride (127 mmol) under nitrogen and themixture is stirred overnight. The mixture is then cooled in an ice bathand excess (diethylamino)sulfur trifluoride is quenched by drop wiseaddition of water. Ethyl acetate (300 mL) is added and the organic layeris washed with saturated aqueous sodium bicarbonate (2×100 mL) followedby water (100 mL). The residue obtained after drying and evaporation ispurified by silica gel chromatography to give the N,N-diethylamidederivative. This is hydrolyzed to the title acid by heating a solutionin ethanol (5 mL) with 10% sodium hydroxide (13 mL) at reflux for 4 h.This sequence is followed by acidification and then extractive work upwith ethyl acetate to give the acid 58 (procedures adopted from Org.Lett., 2001, 3 (25), pp 3987-3990, herein incorporated by reference inits entirety).

Step 2: A stirred solution of 2-(3,5-dimethoxyphenyl)-2,2-difluoroaceticacid (6.63 mmol) in anhydrous DCM (20 mL) is treated with oxalylchloride (19.8 mmol) and 1 drop of dimethylformamide. After vigorouseffervescence ceased, the reaction mixture is stirred for 3 h. Thesolvent is evaporated and traces of oxalyl chloride are removed byrepeated evaporation with anhydrous DCM to give the acid chloride 42.

Step 3: To a stirred solution of2-(3,5-dimethoxyphenyl)-2,2-difluoroacetyl chloride (1 mmol) in MeCN (10ml) is added 3-phenoxypropan-1-ol (3.5 mmol) at 0° C. and the reactionis allowed to warm to room temperature overnight. The product isextracted into DCM and washed with water. The organics are dried withMgSO₄ and filtered through celite. The solvent is removed in vacuo andthe residue is subjected to column chromatography on silica gel to givethe required phenoxy ester 43.

Step 4: Step 4: To a solution of 3-phenoxypropyl2-(3,5-dimethoxyphenyl)-2,2-difluoroacetate (43, 1 mmol) in anhydrousDCM (15 mL), is added boron tribromide (1.2 mmol) at −78° C. undernitrogen atmosphere. The resulting solution is stirred for 15 minutes at−78° C. The cooling bath is removed and the reaction mixture iscontinued to stir for 30 minutes at room temperature. The reaction isquenched with anhydrous methanol (1 mL) at 0° C., washed with water andthe organics are dried with MgSO₄ and filtered through celite. Thesolvents are removed by rotary evaporation and the residue is subjectedto column chromatography on silica gel to give the required compound 44.

Step 5: 3-bromopropyl 2-(3,5-dihydroxyphenyl)-2,2-difluoroacetate (44, 2mmol) is taken in CHCl₃ (75 ml) and to it is added(+)-cis/trans-p-mentha-2,8-dien-1-ol (2.5 mmol) and p-TSA (38 mg) andthe contents are refluxed for 1 hour. The reaction mixture is cooled toroom temperature, washed with water (2×50 ml), dried over MgSO₄ and thenpurified by column chromatography to afford compound 45.

Step 6: To a flask containing 3-bromopropyl2,2-difluoro-2-(1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)acetate(45, 0.71 mmol) is added sodium iodide (2.13 mmol) and acetone (25 ml)and the contents are refluxed for 3 hours. The solvent is evaporated invacuo and the residue is taken in DCM (25 ml), washed with water (2×25ml), dried over MgSO₄ and then purified by column chromatography toafford the iodo compound.

Step 7: 3-iodopropyl2,2-difluoro-2-(1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)acetate(1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate (1.28mmol) is added and the contents are heated to 70° C. for 1 hour. Thesolvent is evaporated in vacuo and the residue is taken in DCM (25 ml),washed with water (2×25 ml), dried over MgSO₄ and the residue ispurified by column chromatography to afford 3-(nitrooxy)propyl2,2-difluoro-2-(1-hydroxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-3-yl)acetate(compound 46).

Example 10: Synthesis of Compound 49

Step 1: To a stirred solution of2-(3,5-dimethoxyphenyl)-2,2-difluoroacetyl chloride (1 mmol) in MeCN (10ml) is added 2-phenoxyethan-1-ol (3.5 mmol) at 0° C. and the reaction isallowed to warm to room temperature overnight. The product is extractedinto DCM and washed with water. The organics are dried with MgSO₄ andfiltered through celite. The solvent is removed in vacuo and the residueis subjected to column chromatography on silica gel to give the requiredphenoxy ester.

Step 2: To a solution of 2-phenoxyethyl2-(3,5-dihydroxyphenyl)-2,2-difluoroacetate (47, 1 mmol) in anhydrousDCM (15 mL), is added boron tribromide (1.2 mmol) at −78° C. undernitrogen atmosphere. The resulting solution is stirred for 15 minutes at−78° C. The cooling bath is removed and the reaction mixture iscontinued to stir for 30 minutes at room temperature. The reaction isquenched with anhydrous methanol (1 mL) at 0° C., washed with water andthe organics are dried with MgSO₄ and filtered through celite. Thesolvents are removed by rotary evaporation and the residue is subjectedto column chromatography on silica gel to give the required compound 48.

Step 3: To a solution of 2-bromoethyl2-(3,5-dihydroxyphenyl)-2,2-difluoroacetate (1 mmol,) in 50 ml DCM isadded ((+)-cis/trans-p-mentha-2,8-dien-1-ol (44, 1 mmol) and 1.5 g ofanhydrous Mg₂SO₄ under an atmosphere of N₂. The contents are cooled to−78° C. and then 0.1% BF₃.Et₂O is added. The mixture is stirred for 1.5hr, brought to 0° C. and then room temperature over 1.5 hr and 2 g ofanhydrous NaHCO₃ is added. Stirring is continued until the reactionmixture is colorless. The reaction contents are filtered, the filtrateis evaporated in vacuo and the residue is purified by columnchromatography to afford cannabidiol 48 (procedures adopted from J. Am.Chem. Soc., 1974, 96 (18), pp 5860-5865 and Tetrahedron Letters 54(2013) 52-54; each herein incorporated by reference in its entirety).

Step: 4: To a flask containing 2-bromoethyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate(48, 1 mmol) is added sodium iodide (2 mmol) and acetone (25 ml) and thecontents are refluxed for 3 hours. The solvent is evaporated in vacuoand the residue is taken in DCM (25 ml), washed with water (2×25 ml),dried over MgSO₄ and then purified by column chromatography to affordthe iodo compound.

Step 5: 2-iodoethyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate(1 mmol) obtained from the previous step is taken in acetonitrile (20ml) and to it silver nitrate (1.28 mmol) is added and the contents areheated to 70° C. for 1 hour. The solvent is evaporated in vacuo and theresidue is taken in DCM (25 ml), washed with water (2×25 ml), dried overMgSO₄ and then purified by column chromatography to afford2-(nitrooxy)ethyl2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate(compound 49).

Example 11: Synthesis of Compound 53a and 53b

Step 1: A mixture of 1-(3,5-dimethoxyphenyl)pentan-1-one (50, 15.8mmol), bis(2-methoxyethyl)aminosulfur trifluoride (127 mmol) and onedrop of ethanol is stirred at 85° C. for 72 hours in a Teflon bottle andquenched by slow addition of water. The mixture is poured into water(100 mL) and extracted with ethyl acetate (100 mL). The organic layer iswashed with water, dried over MgSO₄ and filtered. The filtrate isconcentrated in vacuo and the residue is purified by flash columnchromatography to afford the gem-difluoro compound (procedures adoptedfrom WO 2008060789, herein incorporated by reference in its entirety).

Step 2: To a solution of 1-(1,1-difluoropentyl)-3,5-dimethoxybenzene (1mmol) in anhydrous DCM (15 mL), is added boron tribromide (1.2 mmol) at−78° C. under nitrogen atmosphere. The resulting solution is stirred for15 minutes at −78° C. The cooling bath is removed and the reactionmixture is continued to stir for 30 minutes at room temperature. Thereaction is quenched with anhydrous methanol (1 mL) at 0° C., washedwith water and the organics are dried with MgSO₄ and filtered throughcelite. The solvent is removed in vacuo and the residue is purified bycolumn chromatography on silica gel to give the required compound 51.

Step 3a: To a mixture of 5-(1,1-difluoropentyl)benzene-1,3-diol (51, 3.2mmol) and (+)-cis/trans-p-mentha-2,8-dien-1-ol (44, 3.2 mmol) in benzene(35 ml) is added p-TsOH.H₂O (12 mol %) and the mixture heated to refluxfor 2 h. To this reaction mixture was added a saturated aqueous NaHCO₃solution (25 ml). The mixture is extracted with EtOAc (3×25 ml).Combined organic extracts were washed with water (20 ml) and brine (20ml), dried over MgSO₄, filtered and concentrated under reduced pressure.The crude product is purified by column chromatography to obtaincompound 52a (procedures based on US 20110312903; herein incorporated byreference in its entirety).

Step 3b: To a mixture of 5-(1,1-difluoropentyl)benzene-1,3-diol (51, 3.2mmol) and (+)-cis/trans-p-mentha-2,8-dien-1-ol (44, 3.2 mmol) inanhydrous DCM (25 ml) is added anhydrous MgSO₄ (500 mg) under anatmosphere of N₂. The mixture is cooled to 0° C. followed by theaddition of BF₃.Et₂O (1 mol %) at 0° C. The contents are stirred for 1.5h and subsequently anhydrous NaHCO₃ (1 g) is added, the reaction mixtureis filtered and the solvent removed under reduced pressure. The crudeproduct is purified by column chromatography to obtain the compound 52b.

Step 4: To a solution of(6aR,10aR)-3-(1,1-difluoropentyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol(52a, 3 mmol) or(6aR,10aR)-3-(1,1-difluoropentyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(52b, 3 mmol) in DCM (25 ml) is added triphosgene (1 mmol) at 0° C.under an atmosphere of N₂ (based on procedures adopted from U.S. Pat.No. 4,327,028 and J. Org. Chem. 1991,56, 1549-1553; herein incorporatedby reference in its entirety). The contents are stirred for 1 hour afterwhich they are slowly added via a cannula to a flask containing2-nitroxyethylammonium nitrate (3 mmol, prepared as in US 20130041001;herein incorporated by reference in its entirety) and triethylamine (6.6mmol) in DCM (25 ml) at −15° C. The mixture is stirred at −10° C. for 1h after which water (25 ml) is added, and the organic phase is washedwith aqueous citric acid (10%) and saturated aqueous NaHCO₃, dried overMgSO₄, and evaporated. The crude product is purified by columnchromatography to obtain compound (6aR,10aR)-3-(1,1-difluoropentyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl(2-(nitrooxy)ethyl)carbamate(compound 53a) or(6aR,10aR)-3-(1,1-difluoropentyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl(2-(nitrooxy)ethyl)carbamate(compound 53b).

Example 12: Synthesis of Compounds 55a and 55b

Step 1: To a solution of(6aR,10aR)-3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-7,8,10,10a-tetrahydro-6H-benzo[c]chromen-9(6aH)-one(14, 0.09 mmol, prepared as in WO 2003005960; herein incorporated byreference in its entirety) in 4.5 mL THF and 500 μLi-PrOH at rt is addedNaBH₄ (0.14 mmol). The resulting reaction mixture is stirred at roomtemperature for 40 min and quenched with water and extracted with Et₂O(3×). The combined organic extracts are dried over MgSO₄, solvent isremoved in vacuo and the residue is purified by flash columnchromatography on silica gel to afford the 9-β-hydroxy compound 54a.

Alternatively, to a solution of(6aR,10aR)-3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-7,8,10,10a-tetrahydro-6H-benzo[c]chromen-9(6aH)-one(0.16 mmol, prepared as in WO 2003005960; herein incorporated byreference in its entirety) in 1 mL of THF at −78° C. is added of 1.0 Mpotassium tri-sec-butylborohydride (K-Selectride, 0.32 mmol) in THF. Thereaction mixture is stirred at −78° C. for 2 h, allowed to warm to roomtemperature and stirred for 1 h. The reaction is quenched with 1 mL ofwater and 5 mL of ethanol followed by 2 ml of 15% aqueous NaOH and 2 mLof 30% water. After extraction with Et₂O, the combined extracts arewashed with brine and dried over MgSO₄, solvent is removed in vacuo andthe residue is purified by flash column chromatography on silica gel toafford the 9-α-hydroxy compound 54b.

Step 2: To a flask containing the 9-α or the 9-β isomer of(6aR,10aR)-3-(8-bromo-2-methyloctan-2-yl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-1,9-diol(69, 0.71 mmol) is added sodium iodide (320 mg, 2.13 mmol) and acetone(25 ml) and the contents are refluxed for 3 hours. The solvent isevaporated in vacuo and the residue is taken in DCM (25 ml), washed withwater (2×25 ml), dried over MgSO₄ and then purified by columnchromatography to afford the iodo compound.

Step 3:(6aR,10aR)-3-(8-iodo-2-methyloctan-2-yl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-1,9-diolobtained is taken in acetonitrile (20 ml) and to it silver nitrate (217mg, 1.28 mmol) is added and the contents are heated to 70° C. for 1hour. The solvent is evaporated in vacuo and the residue is taken in DCM(25 ml), washed with water (2×25 ml), dried over MgSO₄ and then purifiedby column chromatography to afford the7-((6aR,9R,10aR)-1,9-dihydroxy-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate(compound 55a) or7-((6aR,9S,10aR)-1,9-dihydroxy-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate (compound 55b).

Example 13: Synthesis of Compound 57

Step 1:(6aR,9R,10aR)-3-heptyl-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol(56, 0.33 mmol, prepared as in J. Med. Chem. 1996, 39, 3790-3796; hereinincorporated by reference in its entirety) is dissolved in anhydrous DCM(3 mL), cooled to 0° C. and triphenylphosphine (0.26 g, 0.99 mmol) andtetrabromomethane (0.4 mL; 1.41 mmol) are added. The reaction mixture isstirred for 3 h after which a portion of methanol and water aresequentially added, and the mixture is extracted with DCM, sequentiallywashed with aqueous NaS₂O₃ and brine, dried over MgSO₄, solvent isremoved in vacuo and the residue is purified by flash columnchromatography on silica gel to afford the bromo compound.

Step 2: To a flask containing(6aR,9R,10aR)-9-(bromomethyl)-3-heptyl-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol(0.71 mmol) is added sodium iodide (2.13 mmol) and acetone (25 ml) andthe contents are refluxed for 3 hours. The solvent is evaporated invacuo and the residue is taken in DCM (25 ml), washed with water (2×25ml), dried over MgSO₄ and then purified by column chromatography toafford the iodo compound.

Step 3:(6aR,9R,10aR)-9-(iodomethyl)-3-heptyl-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol(1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate (1.28mmol) is added and the contents are heated to 70° C. for 1 hour. Thesolvent is evaporated in vacuo and the residue is taken in DCM (25 ml),washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford the title compound2-(((6aR,9R,10aR)-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-3-yl)oxy)ethylnitrate (Compound 57).

Example 14: Synthesis of Compound 62

Step 1:((6aR,10aR)-3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl)methylpivalate (24, prepared as in J. Med. Chem. 1994,37, 3867-3870; hereinincorporated by reference in its entirety) (12 mmol) is dissolved in drydimethylformamide (6 mL) and to this dimethyl-tert-butylsilyl chloride(12.27 mmol) and imidazole (24.6 mmol) are added, and the resultingmixture is stirred for 48 h at room temperature. Water (30 mL) is added,and the mixture is as extracted with Et₂O, dried over MgSO₄, and thesolvent evaporated in vacuo to give the product.

Step 2: To a solution of((6aR,10aR)-3-(8-bromo-2-methyloctan-2-yl)-1-((tert-butyldimethylsilyl)oxy)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl)methylpivalate (0.955 mmol) in anhydrous DCM (9.5 mL) is added 1M solution ofDIBAL-H in toluene (1.2 mmol) dropwise at −78° C. The reaction mixtureis stirred for 2.5 h and then quenched by dropwise addition of potassiumsodium tartrate (10% solution in water) at −78° C. The reaction contentsare warmed to room temperature, extracted with ethyl acetate, theorganic layer is dried over MgSO₄, the solvent evaporated in vacuo andthe residue is purified by flash chromatography to give the product 58.

Step 3: Dry pyridine (2.3 mL) followed by chromic oxide (14.4 mmol) isadded to a solution of DCM-DMF (4:1) (36 mL). The mixture is stirred for15 min and to this((6aR,10aS)-3-(8-bromo-2-methyloctan-2-yl)-1-((tert-butyldimethylsilyl)oxy)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl)methanol(58, 3.6 mmol) in DCM-DMF (4:1) (7.2 mL) is added, and the reactionmixture is stirred at room temperature for 1 h. Ethanol (1.8 mL) isadded, and the mixture is stirred for an additional 10 min and is thendiluted with ethyl acetate (180 mL). The resulting mixture is filteredthrough a sintered-glass funnel, packed with silica (3 cm), with a layerof anhydrous MgSO₄ on top, and eluted with ethyl acetate (600 mL). Theethyl acetate filtrate is washed with dilute hydrochloric acid (1 N) andthen with sodium bicarbonate solution and water. The solvent isevaporated in vacuo to give the aldehyde 59.

Step 4: Using the Pinnick oxidation methodology, sodium chlorite (1mmol) is added portion wise with vigorous stirring to a mixture of(6aR,10aS)-3-(8-bromo-2-methyloctan-2-yl)-1-((tert-butyldimethylsilyl)oxy)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carbaldehyde(59, 1 mmol), 2-methyl-2-butene (60, 1 mmol), saturated aqueouspotassium dihydrogen phosphate (1 mmol), and tert-butyl alcohol (22 mL).The reaction mixture is stirred at room temperature for 5 h. Water (20mL) is added, and the mixture is extracted several times with ethylacetate, dried over MgSO₄, and the solvent is evaporated in vacuo togive the required product.

Step 5: Tetrabutylammonium fluoride (0.6 mmol from a 1.0 M solution inTHF) is added under a nitrogen atmosphere to a cold solution (ice bath)of(6aR,10aS)-3-(8-bromo-2-methyloctan-2-yl)-1-((tert-butyldimethylsilyl)oxy)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid (0.54 mmol) in tetrahydrofuran (THF) (3 mL). The resulting solutionis stirred at 0° C. for 15 min. Water is added, and the mixture isextracted several times with Et₂O. The Et₂O layer is dried, evaporatedin vacuo and the residue is purified by column chromatography to givethe acid 61.

Step 6: To a flask containing(6aR,10aS)-3-(8-bromo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid (61, 0.71 mmol) is added sodium iodide (2.13 mmol) and acetone (25ml) and the contents are refluxed for 3 hours. The solvent is evaporatedin vacuo and the residue is taken in DCM (25 ml), washed with water(2×25 ml), dried over MgSO₄ and then purified by column chromatographyto afford the iodo compound.

Step 7:(6aR,10aS)-3-(8-iodo-2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid (1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents is evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford the title compound(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyl-8-(nitrooxy)octan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene-9-carboxylicacid (Compound 62).

Example 15: Synthesis of Compound 74

Step 1: To a solution of iPr₂NH (29.9 mmol) in 20 mL of THF is added a1.57 M solution of butyllithium in hexanes (29.8 mmol) at 0° C. and themixture is stirred for 5 min. The solution is cooled to −78° C. andpropionitrile (63, 30.0 mmol) is added. The mixture is stirred for 2 h,and 5-phenoxypentyl iodide (64, 30.0 mmol) is added. The mixture is thenis warmed to room temperature and stirred for 24 h. To the reactionmixture is added 50 mL of 1N HCl, and the resulting mixture is extracted3x EtOAc. The combined organic layers are washed with an aqueoussolution of NaHCO₃, dried over MgSO₄, filtered and concentrated and theresulting residue is purified by flash chromatography to give theproduct 65 (procedure adopted from J. Am. Chem. Soc., 2007, 129 (29), pp8948-8949; herein incorporated by reference in its entirety).

Step 2: 2-methyl-7-phenoxyheptanenitrile (65, 12 mmol) in Et₂O (50 mL)at 0° C. is treated with (3,5-dimethoxyphenyl)magnesium bromide (66, 14mmol) and the mixture is stirred for 2 h at 0° C., then at roomtemperature overnight. 3M HCl is added, and after stirring for anadditional 12 h, the mixture is extracted with DCM, washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to give the desiredketone (procedures adopted from U.S. Pat. No. 3,278,606; hereinincorporated by reference in its entirety).

Step 3: To a solution of methyltriphenylphosphonium bromide (32 mmol) inTHF (80 mL) under nitrogen atmosphere is added n-BuLi (15 wt % inhexane, 32 mmol) at 0° C. After stirring for 20 min,1-(3,5-dimethoxyphenyl)-2-methyl-7-phenoxyheptan-1-one (21 mmol) isadded dropwise and after stirring for 24 h and the precipitated solidmaterials are removed by filtration. The filtrate is poured into H₂O (50mL), and extracted with Et₂O (2×50 mL). The combined organic layers arewashed with brine, and dried over anhydrous MgSO₄. The organic layer isconcentrated in vacuo and the residue obtained is used for next stepwithout further purification (procedures adopted from U.S. Pat. No.3,278,606; herein incorporated by reference in its entirety).

Step 4: To a solution of1,3-dimethoxy-5-(3-methyl-8-phenoxyoct-1-en-2-yl)benzene (67, 8.13 mmol)in ethanol (45 mL) is added palladium on carbon (10 mol %) andpressurized to 30 psi of hydrogen for 3 h. The reaction mixture is thenfiltered through a pad of celite, washed with diethyl ether andconcentrated in vacuo to give reduced product (procedures adopted fromU.S. Pat. No. 3,278,606, herein incorporated by reference in itsentirety)

Step 5: To a solution of 11,3-dimethoxy-5-(3-methyl-8-phenoxyoctan-2-yl)benzene (1 mmol) inanhydrous DCM (15 mL), is added boron tribromide (1.2 mmol) at −78° C.under nitrogen atmosphere. The resulting solution is stirred for 15minutes at −78° C. The cooling bath is removed and the reaction mixtureis continued to stir for 30 minutes at room temperature. The reaction isquenched with anhydrous methanol (1 mL) at 0° C., washed with water andthe organics are dried with MgSO₄ and filtered through celite. Thesolvent is removed in vacuo and the residue is purified by columnchromatography on silica gel to give the required compound 68.

Step 6: To a mixture of ethyl isonicotinoylacetate (69, 0.11 mol) and5-(8-bromo-3-methyloctan-2-yl)benzene-1,3-diol (68, 0.11 mole) is addedconcentrated sulfuric acid (46 ml) followed by phosphorus oxychloride(28 ml), the mixture being cooled during the addition. After stirringfor 24 hours, the brown oil is poured into a stirred solution of NaHCO₃and the resulting residue is extracted into DCM. The organic layer iswashed with brine, dried over MgSO₄ and the solvent is evaporated invacuo pressure to give 70 (procedures adopted from U.S. Pat. No.3,726,883; herein incorporated by reference in its entirety).

Step 7: In a certain modification,7-(8-bromo-3-methyloctan-2-yl)-5-hydroxy-4-(pyridin-4-yl)-2H-chromen-2-one(70, 1 mmol) obtained in the previous step is taken in acetonitrile (20ml) and to it silver nitrate (1.28 mmol) is added and the contents areheated to 70° C. for 1 hour. The solvents are evaporated in vacuo andthe residue is taken in DCM (25 ml), washed with water (2×25 ml), driedover MgSO₄ and then purified by column chromatography to afford7-(5-hydroxy-2-oxo-4-(pyridin-4-yl)-2H-chromen-7-yl)-6-methyloctylnitrate 71.

Step 8: Alternatively, to a solution of7-(8-bromo-3-methyloctan-2-yl)-5-hydroxy-4-(pyridin-4-yl)-2H-chromen-2-one(9, 1.0 mmol) taken in anhydrous THF (20 mL) is added methylmagnesiumiodide (3 mmol, 3.0 M in Et₂O) at room temperature under an argonatmosphere. The reaction mixture is stirred at room temperature for 30min and then refluxed for 1.5 h. The reaction is cooled to roomtemperature and quenched by the addition of 20 mL of saturated aqueousNH₄Cl. The THF is removed in vacuo and the residue is dissolved inanhydrous Et₂O (50 mL). The ether solution is washed with water andbrine, dried over MgSO₄, and the solvent is evaporated in vacuo to give72 (procedures adopted from U.S. Pat. No. 3,726,883, J. Med. Chem. 2007,50, 6493-6500, and J. Med. Chem., 1973, 16 (11), 1200-1206; each hereinincorporated by reference in its entirety).

Step 9:5-(8-bromo-3-methyloctan-2-yl)-2-(3-hydroxy-3-methyl-1-(pyridin-4-yl)but-1-en-1-yl)benzene-1,3-diol72 obtained from the previous step is refluxed in glacial acetic acid(20 ml) for 2 hours. The reaction mixture is cooled to room temperatureand poured into water with stirring. The residue that separates isextracted with DCM, washed with water, 15% aqueous NaHCO₃, water andbrine, dried over MgSO₄, the solvent is evaporated in vacuo and theresidue is purified by column chromatography to afford 73 (proceduresadopted from U.S. Pat. No. 3,726,883; herein incorporated by referencein its entirety).

Step 10:7-(8-bromo-3-methyloctan-2-yl)-2,2-dimethyl-4-(pyridin-4-yl)-2H-chromen-5-ol(73, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford7-(5-hydroxy-2,2-dimethyl-4-(pyridin-4-yl)-2H-chromen-7-yl)-6-methyloctylnitrate (Compound 74).

Example 16: Synthesis of Compound 78

Step 1: To a flask containing5-(6-bromo-2-methylhexan-2-yl)benzene-1,3-diol (75, 600 mg, 2.08 mmol)(prepared as in AAPS J. 2004 Oct. 19; 6(4):e30 and procedures based onJ. Med. Chem. 1984,27, 67-71; each herein incorporated by reference inits entirety) is added sodium iodide (936.8 mg, 6.24 mmol) and acetone(25 ml) and the contents are refluxed for 3 hours. The solvent isevaporated in vacuo and the residue taken in DCM (25 ml), washed withwater (2×25 ml), dried over MgSO₄ and the solvent evaporated in vacuo toafford 76 as a dark brown syrup in quantitative yield.

Step 2: 5-(6-iodo-2-methylhexan-2-yl)benzene-1,3-diol (76, 696 mg, 2.08mmol) is taken in acetonitrile (20 ml) and to it silver nitrate (1.06 g,6.24 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvent is evaporated in vacuo and the residue taken in DCM (25 ml),washed with water (2×25 ml), dried over MgSO₄ and the solvent evaporatedin vacuo to obtain 77 as a dark brown syrup (560 mg).

Step 3: 5-(3,5-dihydroxyphenyl)-5-methylhexyl nitrate (77, 560 mg, 2.08mmol) is taken in CHCl₃ (75 ml) and to it is added(+)-cis/trans-p-mentha-2,8-dien-1-ol (44,

380 mg, 2.5 mmol) and p-TSA (38 mg) and the contents are refluxed for 1hour. The reaction contents are cooled to room temperature, washed withwater (2×50 ml), dried over MgSO₄ and then purified by columnchromatography to afford5-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-5-methylhexylnitrate as a light brown syrup (compound 78, 110 mg): ¹H NMR (500 MHz,CDCl₃) δ 6.17-6.53 (2H), 6.02 (s, 1H), 5.59 (br. s., 1H), 4.68 (s, 1H),4.64 (br. s., 1H), 4.57 (s, 1H), 4.35 (t, J=6.59 Hz, 2H), 3.83 (m asb.d., J=8.79 Hz, 1H), 2.38 (ddd, J=2.93, 11, 10.99 Hz, 1H), 2.18-2.31(m, 1H), 2.05-2.17 (m, 1H), 2.02 (s, 1H), 1.72-1.93 (m, 5H), 1.47-1.63(m, 5H), 1.23 (d, J=1.95 Hz, 6H), 1.04-1.18 (m, 2H); MS (ESI⁺) for m/z426 (M+Na).

Example 17: Synthesis of Compounds 83 and 84

Step 1: To a mixture of 2-(3,5-dimethoxyphenyl)-2-methyl-8-phenoxyoctane(4, 2 mmol) in DCM (20 ml) is added a 1M solution of 9-iodo-9-BBN inhexane (79, 6 mmol, 6.1 ml) at 0° C. and then stirred for 3 h at ambienttemperature. To the reaction mixture is added a solution of ethanolamine(7 mmol) in DCM (10 mL to precipitate the 9-BBN.ethanolamine adduct. Themixture is stirred for 1 hour at RT. The reaction is diluted with DCM(50 ml), washed with water (2×25 ml), dried over MgSO₄ and then purifiedby column chromatography to afford the iodoresorcinol 80 (550 mg, 76%).¹H NMR (500 MHz, CDCl₃) δ 6.38 (d, J=1.95 Hz, 2H), 6.18 (s, 1H), 4.75(s, 2H), 3.15 (t, J=6.84 Hz, 2H), 1.69-1.81 (m, 2H), 1.50-1.54 (m, 2H),1.32 (m, 2H), 1.23 (s, 6H), 1.17-1.22 (m, 2H), 1.01-1.11 (m, 2H); MS(ESI⁺) for m/z 363 (M+H).

Step 2: To a solution of 5-(8-iodo-2-methyloctan-2-yl)benzene-1,3-diol(80, 550 mg, 1.5 mmol) and diacetates 81 (prepared in two steps as inAust. J. Chem., 1970, 23, 1069-71 and J. Org. Chem. 1977, 42, 2277-2284;each herein incorporated by reference in its entirety (423 mg, ˜2 mmol,purity) in of CHCl₃ (20 mL) is added p-toluenesulfonic acid monohydrate(380 mg, 2 mmol), and the solution stirred in dark and at roomtemperature for 24 hours. The reaction is diluted with DCM (25 ml),washed sequentially with saturated aqueous NaHCO₃ (1×25 ml), water (2×25ml), dried over MgSO₄ and then purified by column chromatography toafford the bicyclic iodo-derivative 82 (300 mg, 40%). ¹H NMR (500 MHz,CDCl₃) δ 6.28 (s, 2H), 5.19 (s, 2H), 3.95 (t, J=7.81 Hz, 1H), 3.51 (dd,J=19.04, 7.81 Hz, 1H), 3.15 (t, J=6.84 Hz, 2H), 2.61-2.68 (m, 1H),2.56-2.61 (m, 1H), 2.49-2.55 (m, 1H), 2.43-2.48 (m, 1H), 2.28-2.35 (m,1H), 1.75 (m, 2H), 1.44-1.57 (m, 2H), 1.36 (s, 3H), 1.28-1.35, (m, 2H),1.21-1.25 (m, 2H), 1.20 (s, 6H), 1.02-1.13 (m, 2H), 0.99 (s, 3H); MS(ESI⁺) for m/z 499 (M+H).

Step 3:(1R,4R,5R)-4-(2,6-dihydroxy-4-(8-iodo-2-methyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-oneobtained from the previous step (82, 250 mg, 0.5 mmol) is taken inacetonitrile (20 ml) and to it silver nitrate (126 mg, 0.75 mmol) isadded and the contents are heated to 70° C. for 1 hour. The solvent areevaporated in vacuo and the residue taken in DCM (25 ml), washed withwater (2×25 ml), dried over MgSO₄ and the solvent evaporated in vacuoand the residue purified by column chromatography to afford to obtainthe bicyclic nitrateester derivative,7-(4-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3,5-dihydroxyphenyl)-7-methyloctylnitrate (Compound 83, 120 mg, 55%). ¹H NMR (500 MHz, CDCl₃) δ 6.27 (s,2H), 5.10 (s, 2H), 4.41 (t, J=6.59 Hz, 2H), 3.94 (t, J=8.06 Hz, 1H),3.50 (dd, J=18.56, 7.81 Hz, 1H), 2.61-2.67 (m, 1H), 2.57-2.61 (m, 1H),2.49-2.55 (m, 1H), 2.42-2.48 (m, 1H), 2.31 (t, J=5.37 Hz, 1H), 1.62-1.70(m, 2H), 1.46-1.55 (m, 2H), 1.36 (s, 3H), 1.34 (m., 2H), 1.21-1.28 (m,2H), 1.20 (s, 6H), 1.03-1.13 (m, 2H), 1.00 (s, 3H); MS (ESI⁺) for m/z434 (M+H).

Step 4: Compound 83 (120 mg, 0.28 mmol) is dissolved in a 3:1 mixture ofdry DCM and nitromethane (20 mL) and, and the solution is cooled to 0°C. To this is added trimethylsilyl triflate as a 0.29M solution innitromethane (0.34 mL, 0.1 mmol) was added dropwise (procedures adoptedfrom J. Med. Chem. 1996, 39, 3790-3796 and Chem. Commun., 1996,2085-2086; herein incorporated by reference in its entirety). Stirringis continued for 2 h while the temperature is allowed to rise to 25° C.The reaction is quenched with saturated aqueous NaHCO₃/brine (1:1) and60 mL of ether is added and the contents stirred, and the organic layeris separated. The aqueous layer is extracted again with DCM (25 ml), thecombined organic extracts washed with water (2×25 ml), dried over MgSO₄and the solvent evaporated in vacuo and the residue purified by columnchromatography to afford to obtain

the nabilone nitrate ester,7-((6aR,10aR)-1-hydroxy-6,6-dimethyl-9-oxo-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl)-7-methyloctylnitrate (Compound 83, 65 mg, 54%). ¹H NMR (500 MHz, CDCl₃) δ 6.37 (d,J=1.46 Hz, 1H), 6.29 (d, J=1.47 Hz, 1H), 6.25 (s, 1H), 4.40 (t, J=6.84Hz, 2H), 4.02 (d, J=14.16 Hz, 1H), 2.83-2.95 (m, 1H), 2.57-2.69 (m, 1H),2.41-2.53 (m, 1H), 2.10-2.24 (m, 2H), 1.91-2.04 (m, 1H), 1.60-1.70 (m,2H) 1.50-1.60 (m, 3H), 1.48 (s, 3H), 1.28-1.40 (m, 2H) 1.23-1.28 (m,2H), 1.21 (s, 6H), 1.13 (s, 3H), 1.08 (dt, J=7.81, 3.91 Hz, 2H); MS(ESI⁺) for m/z 434 (M+H).

Example 18: Synthesis of Compound 87

Step 1: To a solution of4-(8-bromo-2-methyloctan-2-yl)-2′-(2-hydroxypropan-2-yl)-5′-methoxy-[1,1′-biphenyl]-2,6-diol(11, 1.0 mmol) obtained from scheme 2, in DCM at 0° C. is addedtriethylamine (4 mmol) then methanesulfonyl chloride (3 mmol) dropwise.The mixture is allowed to stir for 75 min at 0° C. then diluted with H₂Oand Et₂O and the layers are separated. The aqueous layer is extractedwith 2x Et₂O, and the combined organic extracts are washed with water(2×25 ml), dried over MgSO₄, the solvents are evaporated in vacuo andthe residue is purified by column chromatography to product 85(procedures adopted from Org. Lett., 2008, 10 (11), pp 2195-2198; hereinincorporated by reference in its entirety).

Step 2: To a solution of4-(8-bromo-2-methyloctan-2-yl)-5′-methoxy-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-2,6-diyldimethanesulfonate (85, 1 mmol) in THF is added MeLi (1.6 M in Et₂O, 10mmol) dropwise at 0° C. The reaction is stirred for 30 minutes and thenquenched with 10% NH₄Cl. The aqueous layer is extracted with 3x Et₂O andthe combined organic extracts are washed with water (2×25 ml), driedover MgSO₄, the solvents are evaporated in vacuo and the residue ispurified by column chromatography to product 86 (procedures adopted fromOrg. Lett., 2008, 10 (11), pp 2195-2198; herein incorporated byreference in its entirety).

Step 3:4-(8-bromo-2-methyloctan-2-yl)-5′-methoxy-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-2,6-diol(86, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue is purified by column chromatographyto afford7-(2,6-dihydroxy-5′-methoxy-2′-(prop-1-en-2-yl)-[1,1′-biphenyl]-4-yl)-7-methyloctylnitrate (compound 87).

Example 19: Synthesis of Compound 88

To a solution of 5-(3,5-dihydroxyphenyl)-5-methylhexyl nitrate (16.0mmol, prepared as in example 16) in 100 ml DCM is added (1R,4S) or(1S,4S) 1-hydroxy-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl)methyl acetate(16.1 mmol, prepared as in ProQuest Ph.D Dissertation 8902359, 1988, 120p; herein incorporated by reference in its entirety) and 2 g ofanhydrous Mg₂SO₄ under an atmosphere of N₂. The contents are cooled to0° C. and then 0.1% BF₃.Et₂O is added. The mixture is stirred for 3 hrat room temperature and 5 g of anhydrous NaHCO₃ is then added. Stirringis continued until the reaction mixture is colorless. The reactioncontents are filtered, the filtrate is evaporated in vacuo and theresidue is purified by column chromatography to afford((1S,65)-2′,6′-dihydroxy-4′-(2-methyl-6-(nitrooxy)hexan-2-yl)-6-(prop-1-en-2-yl)-1,4,5,6-tetrahydro-[1,1′-biphenyl]-3-yl)methylacetate (compound 88) (procedures adopted from J. Am. Chem. Soc., 1974,96 (18), pp 5860-5865 and Tetrahedron Letters 54 (2013) 52-54; eachherein incorporated by reference in its entirety).

Example 20: Synthesis of Compound 91

Step 1: A solution of methyl 1-bromo-3,5-dimethylbenzene (89, 0.5 mmol),(4-(1-(3-bromopropoxy)-2-methyl-1-oxopropan-2-yl)-2,6-dihydroxyphenyl)boronicacid (38, 0.65 mmol), cesium carbonate (2 mmol) in a mixture ofdimethoxyethane (5 mL) and water (0.75 mL) is degassed with argon for 5minutes. Tetrakis(triphenylphosphine)-palladium (0) (10 mol %) is added,the reaction tube is sealed. The reaction is heated in a microwave(Emrys optimizer from Personal Chemistry) at 125° C. (power 300 W) for15 minutes. After cooling, the reaction mixture is diluted with water(30 mL), acidified to pH 5, extracted with DCM (2×15 mL). The combinedorganic layers are passed through a phase separator and concentrated invacuo. The residue is purified with WATERS preparative LC/MSautopurification system to afford the title compound 90 (proceduresadopted from J. Comb. Chem. 2010, 12, 664-669; herein incorporated byreference in its entirety).

Step 2: 3-bromopropyl2-(2,6-dihydroxy-3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-2-methylpropanoate(90, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvent is evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford the title compound 3-(nitrooxy)propyl2-(2,6-dihydroxy-3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-2-methylpropanoate(compound 91).

Example 21: Synthesis of Compound 95

Step 1: To a stirred solution of1-methoxy-3-(2-methyl-6-phenoxyhexan-2-yl)benzene (92, 6.35 mmol)(prepared as in Bioorganic & Medicinal Chemistry 15 (2007) 7850-7864 andprocedures adopted from J. Med. Chem. 1984, 27, 67-71; hereinincorporated by reference in its entirety) in AcOH (30 ml) is added Br₂(12.7 mmol) in AcOH (10 ml) dropwise at room temperature. The mixture isstirred for 4 h at the same temperature. Then, the reaction mixture isquenched with 10% aqueous Na₂S₂O₃ and extracted with 1x 25 ml Et₂O,washed with 1x 25 ml H₂O, the organic extract is washed with 1x 25 mlbrine, dried over MgSO₄, and concentrated in vacuo. The residue ischromatographed to give the brominated product.

Step 2: A solution of1-bromo-2-methoxy-4-(2-methyl-6-phenoxyhexan-2-yl)benzene (0.193 mol) in200 mL of THF is slowly added to magnesium turnings (0.386 mol). Theresultant mixture is refluxed for 20 min and then cooled to −18° C. CuI(9.7 mmol) is added, and stirring is continued for 10 min. To theresultant mixture is slowly added a solution of 2-cyclohexen-1-one(0.193 mol) in 40 mL of THF at such a rate that the reaction temperatureis maintained at <−3° C. The reaction is stirred 30 min and then addedto 500 mL of 2 N HCl and 2 L of ice-water. The mixture is extracted 3x50 mL ether and the combined extract is washed with 2x 100 mL of water,2x 100 mL of saturated NaCl, dried over MgSO₄, and evaporated in vacuo.The residue is purified via column chromatography to give the product93.

Step 3: To a solution of3-(2-methoxy-4-(2-methyl-6-phenoxyhexan-2-yl)phenyl)cyclohexanone (93, 1mmol) in anhydrous DCM (15 mL), is added boron tribromide (1.2 mmol) at−78° C. under nitrogen atmosphere. The resulting solution is stirred for15 minutes at −78° C. The cooling bath is removed and the reactionmixture is continued to stir for 30 minutes at room temperature. Thereaction is quenched with anhydrous methanol (1 mL) at 0° C., washedwith water and the organics are dried with MgSO₄ and filtered throughcelite. The solvent is removed in vacuo and the residue is purified bycolumn chromatography on silica gel to give the bromo phenolintermediate.

Step 4: To a solution of3-(4-(6-bromo-2-methylhexan-2-yl)-2-hydroxyphenyl)cyclohexanone (0.09mmol) in 4.5 mL THF and 500 μL i-PrOH at rt is added NaBH₄ (0.14 mmol).The resulting reaction mixture is stirred at room temperature for 40 minand quenched with water and extracted with 3x Et₂O. The combined organicextracts are dried over MgSO₄, solvent is removed in vacuo and theresidue is purified by flash column chromatography on silica gel toafford the 1-β-hydroxy compound 94a.

Alternatively, to a solution of3-(4-(6-bromo-2-methylhexan-2-yl)-2-hydroxyphenyl)-cyclohexanone (0.16mmol) in 1 mL of THF at −78° C. is added of 1.0 M potassiumtri-sec-butylborohydride (K-Selectride, 0.32 mmol) in THF. The reactionmixture is stirred at −78° C. for 2 h, allowed to warm to roomtemperature and stirred for 1 h. The reaction is quenched with 1 mL ofwater and 5 mL of ethanol followed by 2 ml of 15% aqueous NaOH and 2 mLof 30% water. After extraction with Et₂O, the combined extracts arewashed with brine and dried over MgSO₄, solvent is removed in vacuo andthe residue is purified by flash column chromatography on silica gel toafford the 1-α-hydroxy compound 94b.

Step 5: To a flask containing the 1-α or the 1-β isomer of5-(6-bromo-2-methylhexan-2-yl)-2-((1S)-3-hydroxycyclohexyl)phenol (94,0.71 mmol) is added sodium iodide (320 mg, 2.13 mmol) and acetone (25ml) and the contents are refluxed for 3 hours. The solvent is evaporatedin vacuo and the residue taken in DCM (25 ml), washed with water (2×25ml), dried over MgSO₄ and then purified by column chromatography toafford the iodo compound.

Step 6: 2-((1S)-3-hydroxycyclohexyl)-5-(6-iodo-2-methylhexan-2-yl)phenolis taken in acetonitrile (20 ml) and to it silver nitrate (217 mg, 1.28mmol) is added and the contents are heated to 70° C. for 1 hour. Thesolvent is evaporated in vacuo and the residue is taken in DCM (25 ml),washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford5-(3-hydroxy-4-((1S,3R)-3-hydroxycyclohexyl)phenyl)-5-methylhexylnitrate (Compound 95a) or5-(3-hydroxy-4-((1S,3S)-3-hydroxycyclohexyl)phenyl)-5-methylhexylnitrate (Compound 95b).

Example 22: Synthesis of Compound 98

Step 1: To a flask containing the5-(4-bromobutyl)-4-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-1,3-benzenediol(prepared as in J. Label Compd. Radiopharm 2011, 54 180-184; hereinincorporated by reference in its entirety) (96, 0.71 mmol) is addedsodium iodide (2.13 mmol) and acetone (25 ml) and the contents arerefluxed for 3 hours. The solvent is evaporated in vacuo and the residueis taken in DCM (25 ml), washed with water (2×25 ml), dried over MgSO₄and then purified by column chromatography to afford the iodo compound.

Step 2:(1′S,2′S)-6-(4-iodobutyl)-5′-methyl-2′-(prop-1-en-2-yl)-F,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,4-diol(97, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue is purified by column chromatographyto afford4-((1′S,2′S)-4,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)butylnitrate (compound 98).

Example 23: Synthesis of Compound 100

Step 1: To a flask containing the3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl 3-chloropropane-1-sulfonate(prepared as in ProQuest Ph.D Dissertation 3468427, 2011, 207 p andprocedures adopted from WO 2002026702; each herein incorporated byreference in its entirety) (99, 0.71 mmol) is added sodium iodide (2.13mmol) and acetone (25 ml) and the contents are refluxed for 3 hours. Thesolvent is evaporated in vacuo and the residue taken in DCM (25 ml),washed with water (2×25 ml), dried over MgSO₄ and then purified bycolumn chromatography to afford the iodo compound.

Step 2:(1′S,2′S)-6-(4-iodobutyl)-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4?-tetrahydro-[1,1′-biphenyl]-2,4-diol(97, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue is purified by column chromatographyto afford 3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl3-(nitrooxy)propane-1-sulfonate (compound 100).

Example 24: Synthesis of Compound 103

Step 1: To a flask containing4-hydroxynaphthalen-1-yl)(naphthalen-1-yl)methanone (101, 10 mmol,prepared as in WO 2002/042248; herein incorporated by reference in itsentirety) taken in 100 ml of acetone is added 1,4-diiodobutane (20 mmol)and potassium carbonate (20 mmol), and the mixture is refluxed 24 h. Thesolvent is evaporated in vacuo and the residue is taken in DCM (25 ml),washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue again is purified by columnchromatography to afford the desired O-alkylated compound 102.

Step 2: (4-(4-iodobutoxy)naphthalen-1-yl)(naphthalen-1-yl)methanone(102, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 hour.The solvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue again is purified by columnchromatography to afford 4-((4-(1-naphthoyl)naphthalen-1-yl)oxy)butylnitrate (compound 103).

Example 25: Synthesis of Compound 106

Step 1: To a flask containing 4(1H-indol-3-yl)(naphthalen-1-yl)methanone (104, 10 mmol) taken in 100 mlof acetone is added 1,4-diiodopentane (20 mmol) and potassium carbonate(20 mmol), and the mixture is refluxed 24 h. The solvent is evaporate invacuo and the residue is taken in DCM (25 ml), washed with water (2×25ml), dried over MgSO₄, the solvents are evaporated in vacuo and theresidue again is purified by column chromatography to afford the desiredN-alkylated compound 105.

Step 2: (1-(5-iodopentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (105,1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate (1.28mmol) is added and the contents are heated to 70° C. for 1 hour. Thesolvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue again is purified by columnchromatography to afford 5-(3-(1-naphthoyl)-1H-indol-1-yl)pentyl nitrate(compound 106).

Example 26: Synthesis of Compound 109

Step 1: To a mixture of 6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol(107, 12.8 mmol) and DIPEA (14.08 mmol) in 100 mL dry DCM at 0° C. isadded dropwise a solution of 4-bromobutyryl chloride (12.8 mmol) takenin 20 mL dry DCM under an inert atmosphere. The reaction mixture isallowed to warm up to ambient temperature. After stirring for 16 h,water and DCM were added. The two layers were separated and the organiclayer is dried over MgSO₄, the solvents are evaporated in vacuo and theresidue is purified by column chromatography to afford the bromoderivative 108.

Step 2: To a flask containing the6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-yl 4-bromobutanoate (108,0.71 mmol) is added sodium iodide (2.13 mmol) and acetone (25 ml) andthe contents are refluxed for 3 hours. The solvent is evaporated invacuo and the residue taken in DCM (25 ml), washed with water (2×25 ml),dried over MgSO₄ and then purified by column chromatography to affordthe iodo intermediate.

Step 3: 6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-yl 4-iodobutanoate(1 mmol) from the previous step is taken in acetonitrile (20 ml) and toit silver nitrate (1.28 mmol) is added and the contents are heated to70° C. for 1 h. The solvents are evaporated in vacuo and the residue istaken in DCM (25 ml), washed with water (2×25 ml), dried over MgSO₄, thesolvents are evaporated in vacuo and the residue again is purified bycolumn chromatography to afford6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-yl 4-(nitrooxy)butanoate(compound 109). ¹H NMR (500 MHz, CDCl₃) δ 7.73 (s, 1H), 7.12-7.18 (m,1H), 7.05-7.12 (m, 1H), 6.73 (s, 1H), 6.56 (s, 1H), 4.53 (t, J=6.35 Hz,2H), 2.75 (t, J=7.32 Hz, 2H), 2.57 (t, J=7.81 Hz, 2H), 2.36 (s, 3H),2.15 (t, J=6.59 Hz, 2H), 1.61-1.66 (m, 2H), 1.60 (s, 6H), 1.28-1.38 (m,4H), 0.86-0.94 (m, 3H); MS (ESI⁺) for m/z 442 (M+H).

Example 27: Synthesis of Compound 112

Step 1: To a flask containing(4-methoxyphenyl)(2-methyl-1H-indol-3-yl)methanone (110, prepared as inJ. Med. Chem. 1991,34, 1099-1110, herein incorporated by reference inits entirety) (10 mmol) taken in 100 ml of acetone is added1,4-diiodopentane (20 mmol) and potassium carbonate (20 mmol), and themixture is refluxed 24 h. The solvent is evaporate in vacuo and theresidue is taken in DCM (25 ml), washed with water (2×25 ml), dried overMgSO₄, the solvents are evaporated in vacuo and the residue again ispurified by column chromatography to afford the desired N-alkylatedcompound 111.

Step 2:(1-(5-iodopentyl)-2-methyl-1H-indol-3-yl)(4-methoxyphenyl)methanone(111, 1 mmol) is taken in acetonitrile (20 ml) and to it silver nitrate(1.28 mmol) is added and the contents are heated to 70° C. for 1 h. Thesolvents are evaporated in vacuo and the residue is taken in DCM (25ml), washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue again is purified by columnchromatography to afford5-(3-(4-methoxybenzoyl)-2-methyl-1H-indol-1-yl)pentyl nitrate (compound112). ¹H NMR (500 MHz, CDCl₃) δ 7.79 (d, J=8.79 Hz, 2H), 7.32 (dd,J=14.89, 8.06 Hz, 2H), 7.20 (t, J=7.57 Hz, 1H), 7.03-7.11 (m, 1H), 6.94(d, J=8.79 Hz, 2H), 4.45 (t, J=6.35 Hz, 2H), 4.18 (t, J=7.32 Hz, 2H),3.89 (s, 3H), 2.61 (s, 3H), 2.01 (s, 1H), 1.87 (t, J=7.81 Hz, 2H),1.73-1.82 (m, 2H), 1.47-1.56 (m, 2H); MS (ESI⁺) for m/z 397 (M+H).

Example 28: Synthesis of Compound 117

Step 1: To a magnetically stirred solution ofN-((1s,3s)-adamantan-1-yl)-1H-indazole-3-carboxamide (113, prepared asin U.S. Pat. No. 7,666,867, herein incorporated by reference in itsentirety) (0.51 mmol) in DMF at room temperature is added K₂CO₃ (1.1mmol) and 3-bromopropan-1-ol (0.6 mmol). The resulting mixture isallowed to stir at 90° C. for 1 h. The DMF is evaporated under reducedpressure, and the residue is dissolved in DCM (25 ml), washed with water(2×25 ml), dried over MgSO₄, the solvents are evaporated in vacuo andthe residue (compound 114) is taken directly to the next reaction.

Step 2: To a solution of N-((1s,3s)-adamantan-1-yl)-1-(3-hydroxypropyl)-1H-indazole-3-carboxamide(114, 0.4 mmol) obtained from scheme 2, in DCM at 0° C. is addedtriethylamine (0.6 mmol) then methanesulfonyl chloride (0.5 mmol)dropwise. The mixture is allowed to stir for 75 min at 0° C. thendiluted with H₂O and Et₂O and the layers are separated. The aqueouslayer is extracted with 2x Et₂O, and the combined organic extracts arewashed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue is purified by column chromatographyto product 115. ¹H NMR (500 MHz, CDCl₃) δ 8.39 (d, J=7.81 Hz, 1H), 7.42(d, J=3.42 Hz, 2H), 7.26 (m, 1H), 6.82 (s, 1H), 4.19 (t, J=5.86 Hz, 2H),2.94 (s, 3H), 2.39 (quin, J=6.10 Hz, 2H), 2.20 (br. s., 6H), 2.14 (br.s., 3H), 1.67-1.82 (m, 6H); MS (ESL′) for m/z 432 (M+H).

Step 3: To a flask containing the3-(3-(((1s,3s)-adamantan-1-yl)carbamoyl)-1H-indazol-1-yl)propylmethanesulfonate (115, 0.4 mmol) is added sodium iodide (2 mmol) andacetone (20 ml) and the contents are refluxed for 3 hours. The solventis evaporated in vacuo and the residue taken in DCM (25 ml), washed withwater (2×25 ml), dried over MgSO₄ and then purified by columnchromatography to afford the iodo intermediate 116. ¹H NMR (500 MHz,CDCl₃) δ 8.39 (d, J=8.30 Hz, 1H), 7.47-7.52 (m, 1H), 7.39-7.46 (m, 1H),7.28 (s, 1H), 6.78 (s, 1H), 4.49 (t, J=6.59 Hz, 2H), 3.12 (t, J=6.59 Hz,2H), 2.46 (quin, J=6.47 Hz, 2H), 2.20 (s, 6H), 2.15 (br. s., 3H),1.67-1.84 (m, 6H); MS (ESI⁺) for m/z 464 (M+H).

Step 4:N-((1s,3s)-adamantan-1-yl)-1-(3-iodopropyl)-1H-indazole-3-carboxamide(116, 0.4 mmol) is taken in acetonitrile (20 ml) and to it silvernitrate (0.6 mmol) is added and the contents are heated to 70° C. for 1h. The solvents are evaporated in vacuo and the residue is taken in DCM(25 ml), washed with water (2×25 ml), dried over MgSO₄, the solvents areevaporated in vacuo and the residue again is purified by columnchromatography to afford3-(3-(((1s,3s)-adamantan-1-yl)carbamoyl)-1H-indazol-1-yl)propyl nitrate(compound 117). ¹H NMR (500 MHz, CDCl₃) δ 8.40 (d, J=7.81 Hz, 1H),7.35-7.47 (m, 2H), 7.27 (br. s., 1H), 6.75 (br. s., 1H), 4.50 (t, J=6.59Hz, 2H), 4.42 (t, J=6.10 Hz, 2H), 2.38 (quin, J=6.23 Hz, 2H), 2.20 (s,6H), 2.15 (br. s., 3H), 1.67-1.84 (m, 6H); MS (ESI⁺) for m/z 399 (M+H).

Example 29: Membrane Preparations from Tissue Culture Sources

HEK293 cells expressing hCB1, hCB2 or mCB2 receptor are used formembrane preparations according to the method described in J Neurochem1999, 72, (5), 2032-8, herein incorporated by reference in its entirety.The resulting pellet is resuspended in 10 mM Tris-chloride, pH 7.4 with5 mM MgCl₂ and 2 mM EDTA (TME), and stored at −80° C. for no longer thantwo months. Protein content is assayed by using the Bio-Rad DC proteinassay according to the manufacturer's protocol.

Example 30: Membrane Preparations from Tissue Sources

Frozen rat brains (CB1 source) are obtained from Pel-Freeze Biologicals(Rogers, Ak.) and stored at −80° C. until use. Membranes are preparedaccording to the method described in Brain Res 1981, 226, (1-2), 107-18and adapted as previously reported in J Med Chem 1994, 37, (23), 3867-70and Life Sci 1995, 56, (23-24), 1957-62; each herein incorporated byreference in its entirety.

Example 31: rCB1, hCB2, and mCB2 Binding Assays

The compounds are tested for their ability to bind to CB1 and CB2receptors using rat brain or HEK293 cell membranes expressing hCB2 andmCB2 membrane preparations, respectively, as described in J Med Chem1999, 42, (4), 769-776, J Med Chem 1994, 37, (23), 3867-70 and Life Sci1995, 56, (23-24), 1957-62 (each herein incorporated by reference in itsentirety) via competition-equilibrium binding using [³H]CP-55,940. Theresults are analyzed using nonlinear regression to determine the actualIC₅₀ of the ligand (Prizm by GraphPad Software, Inc.) and the Ki valuesare calculated from the IC₅₀ as described in Biochemical Pharmacology1973, 22, (23), 3099-3108; herein incorporated by reference in itsentirety. For example, the rCB1 affinity data for Δ⁸-THC, Δ⁹-THC,compound 1 and compound 78 are 47 nM, 39 nM, 0.1 nM and 60 nMrespectively; and the hCB2 affinity data for Δ⁸-THC, Δ⁹-THC, compound 1and compound 78 are 39 nM, 40 nM, 1 nM and 35 nM respectively.Competition binding for Compound 1 in rCB1, mCB2 and hCB2 are shown inFIGS. 3, 4 and 5, respectively

Example 32: Covalent Binding Assessment Assay and Electrophilic Labeling

The electrophilic covalent ligand possessing sufficiently highaffinities for the receptors in the competition binding assays areevaluated for their abilities to irreversibly occupy CB1 and/or CB2receptor sites using similar methods described in J Proteome Res. 2011,10(10):4789-98, Chem Biol. 2010, 17(10):1132-42, Chem Biol. 2008,5(11):1207-19, Mol Pharm, 2005, 68(6), 1623-1635, J Med Chem. 2005,48(20):6423-9, J. Org. Chem. 2003, 68 (1), 55-61, J Neurochem. 2000,74(5):2174-81), Life Sci. 1995, 56(23-24):1957-62, J. Med. Chem. 1994,37 (23), 3867-3870, J Med. Chem. 1992, 35 (16), 3076-3079; each hereinincorporated by reference in its entirety. For example, the covalentbinding for Compound 1 to hCB2 is shown in FIG. 2 and the covalentbinding for Compound 84 to rCB1 is shown in FIG. 3.

Example 33: Signal Transduction Assays (cAMP Assay)

Ligands are evaluated for their abilities to behave as agonists,partial-agonists, neutral antagonists, or inverse agonists at CB1 andCB2 sites. HEK293 cells transfected with rCB1, mCB2, or hCB2 receptorare used with the PerkinElmer's Lance ultra cAMP kit following theprotocol as described in J Biomol Screen 1999, 4, (6), 303-308; hereinincorporated by reference in its entirety. The assays are carried out in384-well format using 1000 cells/well. Test compounds are added to wellscontaining stimulation buffer and 2 μM forskolin followed by cellsuspension. After 30 minutes stimulation, the Eu-cAMP tracer andUlight-anti-cAMP are added to the plate and incubated at roomtemperature for 1 h prior to detection via PerkinElmer Envision; dataare analyzed using GraphPad Prism software. For example the cAMP datafor compound 1 and compound 78 using rCB1 is shown in FIG. 7 and FIG. 9.cAMP data for compound 1 and compound 78 using hCB2 is shown in FIG. 8and FIG. 10 respectively.

Example 34: Antinociception in Male Mice

Antinociception is evaluated by measuring response latencies in the warmwater tail-immersion (tail flick) assay using similar methods asdescribed in Arzneimittelforschung 13:502-507 and J Neurosci17:7157-7165; each herein incorporated by reference in its entirety.Response latencies are measured as the amount of time the animal takesto respond to the thermal stimuli. Male CD-1 mice (n=6, Charles RiverBreeding Laboratories, Wilmington, Mass., USA) weighing 30-35 g aregroup housed, 4 to a cage, in a temperature controlled (˜20° C.), animalfacility. Mice are habituated to the vivarium for at least 1 week priorto experiments with a light/dark cycle of 12:12 h (lights on at 7 a.m.)and are acclimatized to study procedures twice, prior to testing. Miceare given food and water ad libitum. Experimentally nave mice are usedfor all procedures and tested during the light phase. All procedures areapproved by The Animal Care and Use Committee of NortheasternUniversity, Boston, Mass., USA. The “Principles of Animal LaboratoryCare” (National Institute of Health 1996) is followed.

a) Fixed dosing: Mice are injected at T=0; and at 1, 3, 5, 7, 24 hourstheir tails are placed into a 52° C. water bath and the time they taketo move “flick” their tails are recorded. Data is expressed as a % of an8 second maximum. For example, FIG. 11 shows comparison of tailimmersion test results for morphine, Δ⁹-THC, and compound 1 in mice.FIG. 12 shows tail immersion test results for compound 1 at 0.1 mg/kgand 1 mg/kg over 24 hours in mice.b) Cumulative dosing: Drugs are administered at 0 min i.e. subsequent tobase-line determinations, 0.1 mg/kg, 1 mg/kg or 1 mg/kg of compound 84,compound 117 or Δ⁹-THC respectively; after 20 min, 0.2 mg/kg, 2 mg/kg or2 mg/kg of compound 84, compound 117 or Δ⁹-THC respectively; and after40 min, 0.7 mg/kg, 7 mg/kg or 7 mg/kg of compound 84, compound 117 orΔ⁹-THC respectively. FIG. 13 and FIG. 14 show tail immersion testresults for compound 84 and compound 117 in comparison to Δ⁹-THC inmice, respectively. FIG. 13 shows tail immersion test results forcompound 84 cumulatively dosed at 1 mg/kg in comparison to Δ⁹-THCcumulatively dosed at 10 mg/kg in mice respectively. FIG. 14 shows tailimmersion test results for compound 117 cumulatively dosed at 10 mg/kgin comparison to Δ⁹-THC cumulatively dosed at 10 mg/kg in mice.

Example 35: Arrestin Assay

Test compounds were screened in U2OS cells permanently expressingβ-arrestin 2-GFP and human GPR55 receptor modified with humanvasopressin V2 receptor tail [GPR55(E)].

β-arrestin2 translocation: For both agonist and antagonist assays, theU2OS cells permanently transfected with β-arrestin 2-GFP and humanGPR55(E) were used to trace β-arrestin translocation upon compoundtreatment. U2OS cells permanently expressing HA-GPR55E and βarr2-GFPwere plated into 96 or 384 glass bottomed well plates in clear MEM. Forthe antagonist assay, compounds in DMSO (final concentration <1%) wereadded to cells 15 min prior to LPI (agonist) addition and the plateswere placed in a 5% 37 degree CO2 incubator (LPI was used at 6 μM). Foragonist evaluation only the compound of interest is placed on the wells.Following 40 minute incubation, the cells are fixed by addingparaformaldehyde to 4%.Image acquisition is performed using the Cellomics Arrayscan VTI HighContent (HC) cell based imaging system and a ×40 lens. Image analysis isdone by using the Batchmode computer software evaluating waveletinformation which reflects the number and intensity of fluorescentaggregation (procedures performed at Duke University and adopted fromhttp://www.ncbi.nlm.nih.gov/books/NBK66153/and J. Biol. Chem. 2009;284(43):29817-27 herein incorporated by reference in its entirety).Comparison of GPR55 antagonist data for Δ⁹-THC, cannabidiol,abn-cannabidiol and compound 78 are shown in Table 1. FIG. 15 describesthe biochemical assay for compound 78 wherein the β-arrestin assessmentof GPR55 activation is shown.

TABLE 1 GPR55 (antagonist assay) data for Δ⁹-THC, cannabidiol,abn-cannabidiol and compound 78. GPR55 EC₅₀ (μM) Δ⁹-THC none cannabidiolnone abn-cannabidiol none compound 78 2-4 LPI (agonist) 6

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

The present disclosure is not to be limited in terms of the particularembodiments described in this application. Many modifications andvariations can be made without departing from its spirit and scope, aswill be apparent to those skilled in the art. Functionally equivalentmethods and compositions within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds compositions or biologicalsystems, which can of course vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

Other embodiments are set forth in the following claims.

1.-60. (canceled)
 61. A compound represented by formula (II):

or a pharmaceutically acceptable salt thereof; wherein: ring C iscarbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a terpene; Gis a bond, C═O, NH, CH₂, CONH, NHCO, C(O)O, OC(O), OCH₂, S, SO, SO₂, orO; ring A is an aromatic ring, heteroaromatic ring, heterocyclic ring,or quinone; R^(2a) and R^(2b) are each independently H, OH, SH, NH₂,CF₃, COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂, or optionally substitutedalkyl, haloalkyl, amine, amide, imide, alkoxy, alkoxy thio, phosphate,phosphonate, carboxyl, formyl, carbamyl, amino, acylamino, amido, imido,aminoalkyl, aminoaryl, heteroarylamino, heterocyclylamino, sulfonate,sufonamide, sulfonyl, thioalkyl, thioaryl, heteroarylthio,heterocyclylthio, phosphonate, phosphate, or acetate; Y is a bond,C(CH₃)₂, CF₂, C═O, CH(alkyl), C(O)O, NHCO, CONH, alkyl, cycloalkyl,heterocyclyl, lactone, lactam, sultam, O, S, SO, SO₂, OSO₂, amine,diazine, alkenyl, or alkynyl group; R³ is absent, or is O, S, SO₂,SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl, alkynyl, cycloalkyl, a carbocyclic,a spirocyclic, heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine,amide, or imide; and V is V¹ or ONO₂, wherein when any of rings A, B orC is substituted with a group comprising ONO₂, V is V¹, otherwise V isONO₂; and V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH,alkoxy, amino, alkylamino, dialkylamino, trialkylamino, aryl,cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl, —C(O)heteroaryl,—C(O)amino, —C(O)(dialkylamino), C(O)(trialkylamino),C(O)(heterocyclyl), C(O)heteroaryl, —OC(O)alkyl, OSO₂H, OSO₂(alkyl),OSO₂(aryl), OSO₂NO₂, OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino),—SC(O)alkyl, —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl,—SC(CH₃)₂C(O)Oaryl, —SC(CH₃)₂C(O)Oheteroaryl,—SC(CH₃)₂C(O)Oheterocyclyl, Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl,NHC(O)aryl, —C(O)H, C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl),SO₂(trialkylamino), SO₂(dialkylamino), a spirocyclic ring, heterocyclyl,heteroaryl, alkylthio, alkylamino, dialkylamino, alkylsulfinyl,alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin grouptethered via an amide bond.
 62. A compound of claim 61 represented byformula (III):

or a pharmaceutically acceptable salt thereof.
 63. A compound of claim61 represented by formula (IV):

or a pharmaceutically acceptable salt thereof.
 64. A compoundrepresented by formula (V):

or a pharmaceutically acceptable salt thereof; wherein: X is C, CH, N,NH, (CH₂)₂N, S, O, SO, SO₂, or CF₂; R¹ is H, OH, ═O, halogen, COOH,nitro, ONO₂, alkyl, haloalkyl, alkenyl, alkynyl, acyl, aryl,heterocyclyl, heteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy,alkenyl, amino, thio, cyano, thiocynato, isothiocynato, carboxyl,formyl, carbamyl, amino, acylamino, amido, imido, aminoalkyl, aminoaryl,heteroarylamino, heterocyclylamino, sulfonate, sufonamide, sulfonyl,thioalkyl, thioaryl, heteroarylthio, heterocyclylthio, phosphonate,phosphate, or acetate. R^(2a) and R^(2b) are each independently H, OH,SH, NH₂, CF₃, COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂, or optionallysubstituted alkyl, haloalkyl, amine, amide, imide, alkoxy, alkoxy thio,phosphate, phosphonate, carboxyl, formyl, carbamyl, amino, acylamino,amido, imido, aminoalkyl, aminoaryl, heteroarylamino, heterocyclylamino,sulfonate, sufonamide, sulfonyl, thioalkyl, thioaryl, heteroarylthio,heterocyclylthio, phosphonate, phosphate, or acetate; Y is a bond,C(CH₃)₂, CF₂, C═O, CH(alkyl), C(O)O, NHCO, CONH, alkyl, cycloalkyl,heterocyclyl, lactone, lactam, sultam, O, S, SO, SO₂, OSO₂, amine,diazine, alkenyl, or alkynyl group; R³ is absent, or is O, S, SO₂,SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl, alkynyl, cycloalkyl, a carbocyclic,a spirocyclic, heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine,amide, or imide; and V is V¹ or ONO₂, wherein when any of rings A, B orC is substituted with a group comprising ONO₂, V is V¹, otherwise V isONO₂; and V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH,alkoxy, amino, alkylamino, dialkylamino, trialkylamino, aryl,cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl, —C(O)heteroaryl,—C(O)amino, —C(O)(dialkylamino), C(O)(trialkylamino),C(O)(heterocyclyl), C(O)heteroaryl, —OC(O)alkyl, OSO₂H, OSO₂(alkyl),OSO₂(aryl), OSO₂NO₂, OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino),—SC(O)alkyl, —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl,—SC(CH₃)₂C(O)Oaryl, —SC(CH₃)₂C(O)Oheteroaryl,—SC(CH₃)₂C(O)Oheterocyclyl, Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl,NHC(O)aryl, —C(O)H, C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl),SO₂(trialkylamino), SO₂(dialkylamino), a spirocyclic ring, heterocyclyl,heteroaryl, alkylthio, alkylamino, dialkylamino, alkylsulfinyl,alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin grouptethered via an amide bond.
 65. A compound of represented by formula(VI):

or a pharmaceutically acceptable salt thereof; wherein: R^(2a) andR^(2b) are each independently H, OH, SH, NH₂, CF₃, COOH, alkoxy,halogen, ONO₂, alkyl-ONO₂, or optionally substituted alkyl, haloalkyl,amine, amide, imide, alkoxy, alkoxy thio, phosphate, phosphonate,carboxyl, formyl, carbamyl, amino, acylamino, amido, imido, aminoalkyl,aminoaryl, heteroarylamino, heterocyclylamino, sulfonate, sufonamide,sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio,phosphonate, phosphate, or acetate; Y is a bond, C(CH₃)₂, CF₂, C═O,CH(alkyl), C(O)O, NHCO, CONH, alkyl, cycloalkyl, heterocyclyl, lactone,lactam, sultam, O, S, SO, SO₂, OSO₂, amine, diazine, alkenyl, or alkynylgroup; R³ is absent, or is O, S, SO₂, SO₂NH, NHSO₂, OSO₂, alkyl,alkenyl, alkynyl, cycloalkyl, a carbocyclic, a spirocyclic,heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine, amide, orimide; and V is V¹ or ONO₂, wherein when any of rings A, B or C issubstituted with a group comprising ONO₂, V is V¹, otherwise V is ONO₂;and V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN, NO₂, OH, alkoxy,amino, alkylamino, dialkylamino, trialkylamino, aryl, cycloalkyl,alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl, —C(O)heteroaryl, —C(O)amino,—C(O)(dialkylamino), C(O)(trialkylamino), C(O)(heterocyclyl),C(O)heteroaryl, —OC(O)alkyl, OSO₂H, OSO₂(alkyl), OSO₂(aryl), OSO₂NO₂,OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino), —SC(O)alkyl, —SO₂alkyl,—SO-alkyl, —SC(CH₃)₂C(O)Oalkyl, —SC(CH₃)₂C(O)Oaryl,—SC(CH₃)₂C(O)Oheteroaryl, —SC(CH₃)₂C(O)Oheterocyclyl, Si(alkyl)₃,—OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H, C(O)Oalkyl, SO₂(amino),SO₂(heterocyclyl), SO₂(trialkylamino), SO₂(dialkylamino), a spirocyclicring, heterocyclyl, heteroaryl, alkylthio, alkylamino, dialkylamino,alkylsulfinyl, alkylsulfonyl, boronic acid, boronate ester, BF₃K, or abiotin group tethered via an amide bond M is CH₂ or alkyl-T¹; L is CH₃or alkyl-T¹; and X is Carbon, CH, N, NH, (CH₂)₂N, S, O, SO, SO₂, or CF₂;R¹ is H, OH, ═O, halogen, COOH, nitro, ONO₂, alkyl, haloalkyl, alkenyl,alkynyl, acyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy,heteroalkoxy, heteroaryloxy, alkenyl, amino, thio, cyano, thiocynato,isothiocynato, carboxyl, formyl, carbamyl, amino, acylamino, amido,imido, aminoalkyl, aminoaryl, heteroarylamino, heterocyclylamino,sulfonate, sufonamide, sulfonyl, thioalkyl, thioaryl, heteroarylthio,heterocyclylthio, phosphonate, phosphate, or acetate; T¹ is H, alkyl,halogen, OH, CF₃, CF₂H, COOH, COOalkyl, alkaloid, immunogen, terpene,O—PO(OX¹)(OY¹), SO₃H, ONO₂ a heterocyclic ring, NQ¹Q¹, or T¹ is anammonium group, wherein said ammonium group can be independentlysubstituted one or more times with a C1 to C6 alkyl radical, or is a C3to C7 heterocycle containing a nitrogen heteroatom for bond formation,wherein the said heterocycle can contain one or more heteroatomsindependently selected from N, O or S, and wherein said heterocycle canbe substituted with one or more independently chosen substituents; Q¹and Q¹ are each independently H, alkyl, or alkyl-ONO₂, or Q¹ and Q¹together are part of a heterocyclic ring having about 4 to about 7 ringmembers and optionally one additional heteroatom selected from O, N orS, or Q¹ and Q¹ together are part of an imide ring having about 5 toabout 6 members; and X¹ and Y¹ are independently H, alkyl-OCO-alkyl,alkyl-O—CO—O-alkyl, alkali metals or alkaline earth metals.
 66. Acompound of claim 61 represented by formula (VII):

or a pharmaceutically acceptable salt thereof; wherein: P is H, alkyl,alkyl-OH or alkyl-ONO₂; X is Carbon, CH, N, NH, (CH₂)₂N, S, O, SO, SO₂,or CF₂; R¹ is H, OH, ═O, halogen, COOH, nitro, ONO₂, alkyl, haloalkyl,alkenyl, alkynyl, acyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy,heteroalkoxy, heteroaryloxy, alkenyl, amino, thio, cyano, thiocynato,isothiocynato, carboxyl, formyl, carbamyl, amino, acylamino, amido,imido, aminoalkyl, aminoaryl, heteroarylamino, heterocyclylamino,sulfonate, sufonamide, sulfonyl, thioalkyl, thioaryl, heteroarylthio,heterocyclylthio, phosphonate, phosphate, or acetate.
 67. A compoundrepresented by formula (VIII):

or a pharmaceutically acceptable salt thereof; wherein: ring C iscarbocyclic, bicyclic, aryl, heterocyclyl, heteroaryl, or a terpene; Gis a bond, C═O, NH, CH₂, CONH, NHCO, C(O)O, OC(O), OCH₂, S, SO, SO₂, orO; R² is H, OH, SH, NH₂, CF₃, COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂,or optionally substituted alkyl, haloalkyl, amine, amide, imide, alkoxy,alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl, amino,acylamino, amido, imido, aminoalkyl, aminoaryl, heteroarylamino,heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl, thioaryl,heteroarylthio, heterocyclylthio, phosphonate, phosphate, or acetate; Yis a bond, C(CH₃)₂, CF₂, C═O, CH(alkyl), C(O)O, NHCO, CONH, alkyl,cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S, SO, SO₂, OSO₂,amine, diazine, alkenyl, or alkynyl group; R³ is absent, or is O, S,SO₂, SO₂NH, NHSO₂, OSO₂, alkyl, alkenyl, alkynyl, cycloalkyl, acarbocyclic, a spirocyclic, heterocyclyl, aryl, heteroaryl, carboxyl,acetate, amine, amide, or imide; V is V¹ or ONO₂, wherein when any ofrings A, B or C is substituted with a group comprising ONO₂, V is V¹,otherwise V is ONO₂; and V¹ is H, F, Cl, Br, I, haloalkyl, N₃, NCS, CN,NO₂, OH, alkoxy, amino, alkylamino, dialkylamino, trialkylamino, aryl,cycloalkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl, —C(O)heteroaryl,—C(O)amino, —C(O)(dialkylamino), C(O)(trialkylamino),C(O)(heterocyclyl), C(O)heteroaryl, —OC(O)alkyl, OSO₂H, OSO₂(alkyl),OSO₂(aryl), OSO₂NO₂, OSO₂(alkyl)CN, OSO₂(alkyl)OH, OSO₂alkylamino),—SC(O)alkyl, —SO₂alkyl, —SO-alkyl, —SC(CH₃)₂C(O)Oalkyl,—SC(CH₃)₂C(O)Oaryl, —SC(CH₃)₂C(O)Oheteroaryl,—SC(CH₃)₂C(O)Oheterocyclyl, Si(alkyl)₃, —OC(O)aryl, NHC(O)alkyl,NHC(O)aryl, —C(O)H, C(O)Oalkyl, SO₂(amino), SO₂(heterocyclyl),SO₂(trialkylamino), SO₂(dialkylamino), a spirocyclic ring, heterocyclyl,heteroaryl, alkylthio, alkylamino, dialkylamino, alkylsulfinyl,alkylsulfonyl, boronic acid, boronate ester, BF₃K, or a biotin grouptethered via an amide bond. W is C(CH₃)₂, CH(CH₃), C═O, CF₂, C═S, C═CH₂,C(cyclopropyl), spirocyclic ring, S, SO, SO₂, or C[CH₃(R⁴)]; R⁴ isalkyl, alkenyl, or alkynyl group; Z is O, S, SO, SO₂, NH, or N-alkyl;and R² is H, OH, SH, NH₂, CF₃, COOH, alkoxy, halogen, ONO₂, alkyl-ONO₂,alkyl, haloalkyl, amine, amide, imide, alkoxy, alkoxy thio, phosphate,phosphonate, carboxyl, formyl, carbamyl, amino, acylamino, amido, imido,aminoalkyl, aminoaryl, heteroarylamino, heterocyclylamino, sulfonate,sufonamide, sulfonyl, thioalkyl, thioaryl, heteroarylthio,heterocyclylthio, phosphonate, phosphate, or acetate;
 68. A compound ofclaim 61 represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; wherein: Q is C or N. 69.The compound of claim 61, wherein C is:


70. The compound of claim 61, wherein A is:


71. The compound of claim 61, wherein A is:


72. The compound of claim 61 wherein: C is aromatic and A is aromatic,and G is C═O; C is aromatic and A is heteroaromatic, and G is C═O; C isaromatic and A is heteroaromatic, and G is CONH; C is heterocyclic and Ais heteroaromatic, and G is C═O; C is heterocyclic and A isheteroaromatic, and G is C═O; C is alkyl and A is heteroaromatic, and Gis C═O; C is carbocyclic and A is heteroaromatic, and G is C═O; C isalkyl and A is heteroaromatic, and G is CONH; C is heteroaromatic and Ais heteroaromatic, and G is N(alkyl)SO₂; C is aromatic and A isheteroaromatic, and G is NH; C is bicyclic ring and A is aromatic, and Gis O; C is bicyclic ring and A is aromatic, and G is a direct bond; C isa terpene; C is carbocyclic and W is optionally present; C isheteroaromatic and A is heteroaromatic, and G is OCH₂; C is heterocyclicand A is aromatic, and G is CH₂; C is aromatic and A is heterocyclic,and G is CH₂; C is carbocyclic and A is heteroaromatic, and G is a COOor OCO; C is heterocyclic and A is aromatic, and G is a direct bond; Cis heterocyclic and A is heteroaromatic, and G is a direct bond; C is aterpene and A is aromatic, and G is a direct bond; C is a terpene and Ais quinone, and G is a direct bond; C is a terpene and A is aromatic,and G is a direct bond; C is heterocyclic and A is aromatic, and G is adirect bond; C is aromatic and A is aromatic, and G is a direct bond; Cis aromatic and A is heterocyclic, and G is a direct bond; C is alkyland A is heteroaromatic, and G is a direct bond; C is a terpene and A isaromatic, and G is a direct bond; C is bicyclic and W is C═O; or C iscarbocyclic, B is carbocyclic and A is aromatic.
 73. A compositioncomprising a compound of claim 61 and at least one pharmaceuticallyacceptable excipient.
 74. A method of modulating activity of acannabinoid 1 (CB1), cannabinoid 2 (CB2) or GPR55 receptor, the methodcomprising contacting the cannabinoid 1 (CB1), cannabinoid 2 (CB2), orGPR55 receptor with the compound of claim 61.